Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]I>>[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[C:11]([OH:13])=[O:12]
Reactant: ClCCCCI
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(CCCCCl)C(=O)O)cc1
Yield: 36.6 %

Procedure:
Step AAN (1): 2-(4-Ethoxyphenyl)acetic acid (2.00 g, 11.1 mmol) was deprotonated with NaHMDS 2.0 M in THF (12.5 mL, 25.0 mmol) and reacted with 1-chloro-4-iodobutane (1.49 mL, 12.2 mmol) using a procedure analogous to Step AC (1) and after silica gel column chromatography (30-80% EtOAc/hexanes) afforded 6-chloro-2-(4-ethoxyphenyl)hexanoic acid (1.10 g, 4.06 mmol, 37% yield) as a pale-yellow oil. LC-MS (M+Na)+ 293.1.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([NH2:30])=[N:27][CH:26]=2)=[CH:21][CH:20]=1.[Br:32][C:33]1[S:34][C:35]([C:38](O)=[O:39])=[CH:36][N:37]=1>CN(C=O)C.CCOC(C)=O>[Br:32][C:33]1[S:34][C:35]([C:38]([NH:30][C:28]2[S:29][C:25]([C:22]3[CH:21]=[CH:20][C:19]([CH3:31])=[CH:24][CH:23]=3)=[CH:26][N:27]=2)=[O:39])=[CH:36][N:37]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: Cc1ccc(-c2cnc(N)s2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc(NC(=O)c3cnc(Br)s3)s2)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.55 g, 2.2 mmol), DIEA (0.37 g, 2.9 mmol) and 5-p-tolylthiazol-2-amine (0.27 g, 1.44 mmol) were added to a suspension of 2-bromothiazole-5-carboxylic acid (0.30 g, 1.44 mmol) in DMF (5 mL). The resulting solution was stirred at RT till completion of the reaction. The mixture was then diluted with AcOEt, washed with water, dried with Na2SO4 and concentrated. The crude product was purified by column (30% AcOEt/PE), yielding 2-bromo-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (250 mg, 46%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12](/[CH:14]=[C:15](/[NH2:17])\[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>CO.CCOC(C)=O.Cl.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C/C(N)=C\c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)Cc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reaction time: 7 h
Yield: 58 %

Procedure:
To a solution of (E)-1-(5-(3,4-dichlorophenyl)furan-2-yl)prop-1-en-2-amine (2.72 g, 9.12 mmol) in MeOH (135 ml), EtOAc (100 ml) and 6.5% HCl (g) in MeOH (32 ml) was added 10% Pd/C (1.09 g). The mixture was hydrogenated under pressure (3.3 bar, Parr hydrogenating apparatus) for 7 h. The reaction mixture was filtered through Celite, evaporated and purified by chromatography (CombiFlash, silica column, eluent: 5-20% MeOH/DCM) to yield 0.811 g (29%) of the title compound as an HCl salt. 1H-NMR (400 MHz; d6-DMSO): δ 1.21 (d, 3H), 2.90 (dd, 1H), 3.04 (dd, 1H), 3.55 (q, 1H), 6.44 (d, 1H), 7.09 (d, 1H), 7.68 (m, 2H), 7.93 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])[CH2:7][C:6]=2[CH:27]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Reaction time: 16 h

Procedure:
To a stirred solution of the compound from example 5 (270 mg, 0.71 mmol) in dichloromethane (20 mL) was added triethylamine (118.8 μL, 0.86 mmol) followed by dimethylsulfamoyl chloride (84 μL, 0.78 mmol) and the reaction mixture was stirred for 16 hours. Dimethylsulfamoyl chloride (84 μL, 0.78 mmol) was then added and the reaction stirred for a further 72 hours. The reaction was diluted with water (20 mL) and the phases separated. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using ethyl acetate and then dichloromethane methanol (95:5) as eluent gave the product as a white crystalline solid, 217 mg (63%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1>CO>[Br:1][C:2]1[C:10]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3[nH]cc(Br)c23)c1
Temperature: 125 °C
Yield: 39.8 %

Procedure:
To 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.13 g, 0.57 mmol) in dry methanol (2 ml) was added m-aminophenyl acetylene (0.08 g, 0.68 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (10 g, 40 mm mesh) using 3% methanol/methylene chloride to afford the title compound as a yellow powder (71 mg, 39%). TS-MS: 314 (MH+); anal. RP18-HPLC RT: min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.O>ClCCl>[CH2:32]([O:33][C:34]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[N:10]2)=[C:2]([F:1])[CH:7]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
200 mg of 2-(1-(2-fluoro-4-aminophenyl)-1H-pyrazol-4-yl)pyridine (25f) was dissolved in 5 mL dichloromethane, with addition of 194.3 mg K2CO3. Then, 990 μL Cbz-Cl was slowly dropped into the resultant mixture maintained in an ice bath. After completion of the addition, the ice bath was removed. The reaction mixture was warmed naturally to room temperature and reacted for 2 hours. TLC monitoring was performed to determine the completion of the reaction, after which water was added into the reaction solution. The mixture was extracted with dichloromethane for three times. The combined organic phase was dried and rotary evaporated. The residue obtained was repeatedly washed with petroleum ether until the excess Cbz-Cl was completely removed, thereby affording 260 mg of a light yellow solid, with a yield of 95.1%.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[NH:14][CH:13]=[N:12][C:11]=3[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[CH:1]1([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[N:14]([CH2:25][C:26](=[O:28])[CH3:27])[CH:13]=[N:12][C:11]=3[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:8]2=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCl
Reactant: O=c1c2[nH]cnc2n(CC2CCCC2)c(=O)n1CC1CCCC1
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCCC1)c(=O)n2CC1CCCC1

Procedure:
1,3-Di-cyclopentylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclopentylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 144° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[C:3]([CH2:2][O:16][C:17]2[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1cccnc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccccc2Cl)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(2-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 1.50 equiv) in CH3CN. (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The residue was purified by prep-HPLC. This resulted in 86.2 mg (11%) of 5-[[2-(2-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a brown oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][CH2:14][C:15]1[CH:20]=C(C(O)=O)[CH:18]=[CH:17][C:16]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>C(Cl)Cl>[CH3:12][O:13][CH2:14][C:15]1[CH:20]=[C:1]([C:2]([Cl:4])=[O:3])[CH:18]=[CH:17][C:16]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Cl)ccc1-c1ccccc1C
Reaction time: 15 h
Yield: 98 %

Procedure:
Oxalyl chloride (2.0 mL, 23.6 mmol) and anhydrous DMF (0.060 mL, 0.78 mmol) were added into a solution of 2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylic acid (2.0 g, 7.8 mmol) in anhydrous DCM (40 mL). After 15 hours at RT, the reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (2.1 g, quantitative), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNC3CCNCC3)ccc21
Yield: 194.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (34.5 mg, 0.0840 mmol) was dissolved in acetonitrile (1 mL), and the solution was treated with 4-amino-1-(tert-butoxycarbonyl)piperidine (70.1 mg, 0.350 mmol), acetic acid (0.100 mL, 1.74 mmol) and sodium triacetoxyborohydride (44.0 mg, 0.208 mmol). The reaction mixture was added with water and sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(piperidin-4-ylaminomethyl)indol-2-yl]isoindolinone (80.8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)C[C:4]=2[CH:3]=1.[OH-].[Na+].O1CCCCC1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1.BrCCO>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CS(C)=O.CCCCCC.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:29]([CH2:30][CH2:25][OH:24])([CH2:28][CH2:27][OH:26])[C:13]=2[CH:14]=1
Reactant: C1CCC(OC2CCCCO2)OC1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: OCCBr
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OCCC1(CCO)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 35 °C
Yield: 70.8 %

Procedure:
A mixture containing 5.0 grams of 2,7-dibromofluorene, 3.1 grams of sodium hydroxide and 0.35 grams of Benzyltriethylammonium chloride in 50 ml of dimethylsulfoxide was stirred and to it was added 9.7 grams of the tetrahydropyranyl ether of 2-bromoethanol. The temperature rose slowly to 50° C. The temperature was maintained at 35° C. for 1 hr after which the mixture was added to 100 ml of water and 50 ml of ethyl acetate and 50 ml hexane. The organic layer was removed washed 2× with 100 ml of water and dried over sodium sulfate. The solvent was removed and 150 ml of ethanol added followed by 0.5 grams p-toluene sulfonic acid. The mixture was stirred at 70° C. for 30 min. The mixture was cooled and treated with aqueous potassium carbonate to ˜pH8. The solvent was removed and the residue treated with 50 ml of 1;1 ethyl acetate:hexane and 25 ml of water the solid was filtered and washed with water. Recrystallization from 1:1 ethyl acetate hexane to give 4.5 grams of 2-[2,7-dibromo-9-(2-hydroxy-ethyl)-9H-fluoren-9-yl]-ethanol which was esterified by the process described in example 1 to give 3.8 grams of Acrylic acid 2-[9-(2-acryloyloxy-ethyl)-2,7-dibromo-9H-fluoren-9-yl]-ethyl ester(4). This product was verified by NMR analysis to be present and pure.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O:6][CH:7](OC)[CH2:8][CH2:9][CH2:10][CH:11]=O>CCOC(C)=O.CCCCCC>[N+:1](/[CH:4]=[CH:11]/[CH2:10][CH2:9][CH2:8][CH:7]=[O:6])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C/[N+](=O)[O-]
Yield: 65.9 %

Procedure:
Prepared according to the general procedure A from nitromethane 112a (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 66% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:15]=1)[CH2:9][CH2:8]2)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>C(Cl)Cl>[CH:38]([O:37][C:35]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:16]2[CH:15]=[C:14]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH2:8][CH2:9]3)[N:19]=[CH:18][N:17]=2)[CH2:22][CH2:23]1)=[O:36])([CH3:40])[CH3:39]
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(NC2CCNCC2)ncn1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6c (104 mg, 0.21 mmol) and triethylamine (0.1 mL, 3.3 eq) in 1 mL of DCM, was added isopropyl chloroformate (0.24 mL, 1.1 eq). The mixture was stirred at room temperature for 2 h. The crude mixture was poured onto silica and eluted with ethyl acetate/hexane then chromatographed over a silica gel column (elution with 25-100% ethyl acetate and 0.1% TEA in hexanes) and finally purified on preparative HPLC to give 6-1, LC-MS 460.4 (MH+), tR=4.50 (Method 4). EC50: 611 nM.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[C:16]([C:20]1[CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26])([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[C:16]([C:20]1[CH:28]=[C:24]([CH:23]=[C:22]([C:29]([N:11]2[CH2:10][CH2:9][CH:8]([O:7][C:6]3[CH:14]=[CH:15][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:13][CH2:12]2)=[O:30])[CH:21]=1)[C:25]([OH:27])=[O:26])([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)cc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenoxy)piperidine hydrochloride (100 mg, 0.40 mmol), 5-(tert-butyl)isophthalic acid (358 mg, 1.61 mmol), and N,N-diisopropylethylamine (0.28 mL, 1.61 mmol) in N,N-dimethylformamide (3 mL) was add HBTU (183 mg, 0.48 mmol) at room temperature. After stirring at 60° C. for 2 hours, the mixture was poured into water (5 mL). This was extracted with ethyl acetate (5 mL) and washed with water (5 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (eluting with dichloromethane/methanol=7:1) to give 121 mg (72% yield) of the title compound as a white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][NH:30][C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH:4]3[C:9]4[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=4[CH2:7][CH2:6][O:5]3)[C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Reactant: N#Cc1ccc2c(c1)CCOC2CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-(2-oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.454 g, 2.26 mmol) in methanol (30 mL) was added (3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine (0.61 g, 2.49 mmol), and the mixture stirred for 10 min. Sodium cyanoborohydride (0.157 g, 2.49 mmol) and acetic acid (0.25 mL) were added and the mixture stirred for 18 h. A further portion of sodium cyanoborohydride (0.20 g) was added and the reaction stirred for 6 h. The mixture was quenched with water, and the solvent removed in vacuo. Water was added and the mixture extracted with chloroform, the organic extracts dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative LC-MS to yield the title compound as a yellow oil.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:9][C@H:8]1[C:10]1[N:15]=[C:14]2[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2=[CH:12][CH:11]=1)(=O)=O.[CH3:26][N:27]1[C:31](=[O:32])[CH2:30][NH:29][C:28]1=[O:33].[H-].[Na+]>CN(C=O)C>[CH3:22][C:20]([CH3:21])([CH3:23])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C@@H:8]3[CH2:9][C@H:7]3[CH2:6][N:29]3[CH2:30][C:31](=[O:32])[N:27]([CH3:26])[C:28]3=[O:33])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: CN1C(=O)CNC1=O
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3COS(C)(=O)=O)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN(C[C@@H]2C[C@H]2c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
{(1R,2R)-2-[1-(2,2-Dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclopropyl}methyl methanesulfonate (31-5, 68 mg, 0.18 mmol, 1.0 equiv) was added to anhydrous DMF (0.92 mL) and cooled to 0° C. 3-Methylimidazolidine-2,4-dione (31-6, 105 mg, 0.92 mmol, 5.0 equiv) and NaH (37 mg, 0.92 mmol, 5.0 equiv, 60% dispersion in oil) were added sequentially and the resulting mixture was warmed to RT. After 18 h, LCMS showed complete consumption of 31-5. Purification by reverse-phase HPLC (10-100% 0.1% TFA in H2O:CH3CN) afforded 31-7 as a colorless oil. MS m/z (M+H): calculated=332.1969; observed=332.1971.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:26]
Reactant: O=C(Cl)c1ccccc1F
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1F
Yield: 83.5 %

Procedure:
0.5 g (0.0026 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046.mol). of triethylamine were dissolved in 20 ml of toluene and treated with 0.32 ml (0.0027 mol) of 2-fluoro-benzoyl chloride. The mixture was boiled at reflux for 6 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:1). 0.68 g (83%) of 1-benzyl-piperidin-4-yl 2-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([NH:12][C:13]1[CH:18]=[C:17]([C:19]([O:21]CC)=[CH2:20])[N:16]=[C:15]([C:24]([O:26][CH3:27])=[O:25])[C:14]=1[Cl:28])(=[O:11])[CH3:10]>C1COCC1.O>[C:9]([NH:12][C:13]1[CH:18]=[C:17]([C:19](=[O:20])[CH2:21][Br:1])[N:16]=[C:15]([C:24]([O:26][CH3:27])=[O:25])[C:14]=1[Cl:28])(=[O:11])[CH3:10]
Reactant: C=C(OCC)c1cc(NC(C)=O)c(Cl)c(C(=O)OC)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(C(=O)CBr)cc(NC(C)=O)c1Cl
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
N-Bromosuccinimide (0.377 g, 2.13 mmol) was added all at once to a solution of methyl 4-acetamido-3-chloro-6-(1-ethoxyvinyl)pyridine-2-carboxylate (0.636 g, 2.13 mmol) in THF (40 mL) and water (2 mL) at room temperature. After 15 minutes, the reaction mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was separated, dried (MgSO4), and concentrated to provide methyl 4-acetamido-3-chloro-6-(bromoacetyl)pyridine-2-carboxylate (0.714 g, 2.04 mmol). 1H NMR (CDCl3): δ 9.12 (s, 1H), 7.99 (br.s, 1H), 4.82 (s, 2H), 4.06 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:36](=[O:35])[CH2:37][OH:38])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f9) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>O>[Cl:11][C:9]1[N:10]=[C:2]([NH:14][CH2:12][CH3:13])[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCN
Solvent: O
Product: CCNc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml (3.45 mol) of a 70% solution of ethylamine in water is heated at 50° C. for ten hours. The excess amine is then evaporated off under reduced pressure, and aqueous 10% acetic acid solution is then added until the product precipitates. The beige-coloured solid is filtered off by suction, rinsed with cold water and oven-dried. 10.5 g of the expected product are obtained. Yield=62%. Melting point: 158-160° C.