Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)=[C:9](Cl)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[NH2:22].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[C:9]([CH:8]=1)=[N:22][N:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[C:13]=2[CH2:14][CH:15]1[CH2:17][CH2:16]1)=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: NNc1ccncc1
Reactant: CC(C)(C)OC(=O)c1ccc(C#CC2CC2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)c1ccc2c(CC3CC3)n(-c3ccncc3)nc2c1
Yield: 41.8 %

Procedure:
The reaction was performed according to example 1 using 138.4 mg 3-chloro-4-cyclopropylethynyl-benzoic acid tert-butyl ester, 101.9 mg 4-hydrazinopyridine hydrochloride (1.4 equiv.) and 456.2 mg Cs2CO3 (2.8 equiv.) with a reaction time of 4 hours at 110° C. This afforded 73.0 mg (42%) of the title compound. 1H-NMR (DMSO-d6) δ 0.14-0.18 (m, 2H), 0.40-0.45 (m, 2H), 0.91-1.00 (m, 1H), 1.59 (s, 9H), 3.16 (d, 2H, J=6.8 Hz), 7.54 (dd, 1H, J=8.9, 1.3 Hz), 7.81 (dd, 2H, J=4.5, 1.6 Hz), 7.99 (dd, 1H, J=8.9, 0.8 Hz), 8.85 (dd, 2H, J=4.5, 1.6 Hz); HRMS (FAB): Calculated for C21H24N3O2 (M+H+) 350.1869, found 350.1864.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].Cl[CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].Cl>O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH2:15][C:16]([OH:18])=[O:17])([CH3:12])[CH3:11]
Reactant: O=C(O)CCl
Reactant: CC(C)c1cccc(C(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1OCC(=O)O
Yield: 90.2 %

Procedure:
16.4 g of 2,6-diisopropylphenol, 10.0 g of chloroacetic acid, 10.0 g of sodium hydroxide and 300 ml of water were put into a round bottom flask and stirred under reflux for 6 hours. The reaction mixture was cooled and then the pH was adjusted to from 3 to 4 with a dilute hydrochloric acid. The precipitate thereby formed was collected by filtration, washed with water and dried to obtain 20.5 g of crude crystals. The crude crystals were recrystallized from diethyl ether-hexane to obtain 19.6 g (yield: 88.3%) of the desired compound as colorless prism crystals. Melting point: 84°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([CH:7]=[CH2:8])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].B1C2CCCC1CCC2.[OH-:22].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][OH:22])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: C=Cc1cc(Cl)c(C(=O)OC)[nH]1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c(CCO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A stirred solution of methyl 3-chloro-5-ethenyl-1H-pyrrole-2-carboxylate (0.100 g, 0.539 mmol) in THF (5 mL) was treated with 9-BBN (5.39 mL, 2.15 mmol). The reaction was stirred at RT overnight. The reaction mixture was treated with 1 mL of 1N NaOH and 1 mL of 30% H2O2 and stirred. The reaction mixture was partitioned between EtOAc and a solution of sodium metabisulfite. The organic layer was separated, dried over MgSO4 and evaporated to a residue. The residue was taken up in 1N LiOH (1 mL), MeOH (1 mL) and THF (1 mL) and heated until the acid was formed as seen on TLC. The reaction was evaporated, acidified and extracted with EtOAc. The organic layer was separated and dried over MgSO4 to afford methyl 3-chloro-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylate (0.028 g, 27%) as a solid. LCMS: m/z=188.0 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCc1ccccn1
Product: Clc1nc(Cl)nc(NCCc2ccccn2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 2-(2-aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: FC(F)O[C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1.[Li+].[OH-:20].Cl>C1COCC1.CO>[O:20]=[C:4]([CH3:9])[CH2:5][CH2:6][C:9]1[CH:4]=[CH:5][C:6]2[N:7]([C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)[CH:8]=1
Reactant: CCOC(=O)c1cnc2cc(OC(F)F)ccn12
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 7-(difluoromethoxy)imidazo[1,2-a]pyridine-3-carboxylate (79) (150 mg, 0.585 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 5 mL) was heated at 60° C. for 45 minutes. The reaction was cooled to room temperature and the pH was adjusted between 4-5 with 1N HCl. The solvent was partially reduced and the crude product was purified by reverse phase preparative HPLC to yield 6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxylic acid (80). MS m/z 229.03 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:29]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=[C:26]([O:41][CH3:42])[N:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:29]1[C:24]([O:23][CH3:22])=[N:25][C:26]([O:41][CH3:42])=[CH:27][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)n1
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)c(OC)n1
Yield: 86.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and [(2,6-dimethoxypyridin-3-yl)methyl](4-isopropylphenyl)amine (0.43 g) as starting materials, 5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71 g) was obtained.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:67]([O:71][C:72]([N:74]1[CH2:79][CH2:78][N:77]([C:80]2[CH:85]=[CH:84][C:83]([CH:86]=O)=[CH:82][CH:81]=2)[CH2:76][CH2:75]1)=[O:73])([CH3:70])([CH3:69])[CH3:68]>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:86]([C:83]3[CH:82]=[CH:81][C:80]([N:77]4[CH2:76][CH2:75][N:74]([C:72]([O:71][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:73])[CH2:79][CH2:78]4)=[CH:85][CH:84]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 32.8 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.057 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.17 mmol, 0.17 mL) and 4-(4-formylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.1 eq, 0.063 mmol, 20 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (11 mg, 41%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.43 (s, 9H, C(CH3)3), 7.08 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 7.55 (dd, J=8.5, 4.4 Hz, 1H, pyridine H-5), 7.99 (d, br, J=8.4 Hz, 1H, pyridine H-4), 8.03 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 8.14 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.69 (d, J=4.4 Hz, 1H, pyridine H-6), 8.75 (s, br, 1H, pyridine H-2), 13.36 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH:12]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O>[N:44]([C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][CH:12]([CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)/[CH:13]=[CH:14]/[P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(Cl)ncnc21)OC(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OP(=O)(/C=C/C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cn1cnc2c(N=[N+]=[N-])ncnc21)OC(C)C
Temperature: 70 °C
Yield: 75.4 %

Procedure:
A mixture of (E)-6-chloro-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]purine (244 mg, 381 μmol) and sodium azide (25 mg, 381 μmol) in N,N-dimethylformamide (7 ml) was heated at 70° C. for 2.8 h. The solvent was removed and the residue purified by column chromatography on silica gel eluting with acetone-hexane (1:4, 1:1) to give (E)-6-azido-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]purine as a gum (186 mg, 75%); λmax (EtOH) 282 (10,363)nm; υmax (film) 2980, 2935, 2155, 1640, 1375, 1250 and 1110 cm-1 ; δH (CDCl3) 1.00-1.40 (21H, m, CH3), 3.05 (1H, m, CH), 3.70 (2H, m, CH2O ), 4.30-4.80 (4H, m, CH2N and CH(CH3)), 5.58 (1H, m, PCH= CH) , 6.70 (1H, m, PCH=CH) , 7.30-7.70 (10H, m, C6H5) , 7.86 (0.35H, s, H-2/H-8), 8.05 (0.65H, s, H-2/H-8), 8.64 (0.35H, s, H-2/H-8), 9.44 (0.65H, s, H-2/H-8)*; FABMS (TDE/Na) 670 (MNa+), 648 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([CH2:1][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[S:3][CH:4]=1
Reactant: CCCC(=O)OCC
Reactant: Cc1csc(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)Cc1nc(C)cs1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.00 g (26.5 mmol) of 2,4-dimethylthiazole are dissolved in 30 ml of abs. THF and, at −78° C., 11.7 ml (29.2 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 5.23 g (45.1 mmol) of ethyl butyrate are added as solution in 15 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 5:1). 3.0 g (62% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([CH2:3][N:4]([CH3:24])[C:5](=[O:23])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH3:13])=[CH:8][C:7]=1[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])#[N:2].C1(C)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[C:1]([C:3]1[N:4]([CH3:24])[C:5](=[O:23])[C:6]2[C:7]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:8][C:9]([CH3:13])=[C:10]([CH3:12])[CH:11]=2)#[N:2]
Reactant: Cc1cc(C(=O)c2ccccc2C)c(C(=O)N(C)CC#N)cc1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc2c(-c3ccccc3C)c(C#N)n(C)c(=O)c2cc1C
Reaction time: 7 h
Yield: 73.4 %

Procedure:
A mixture of the compound obtained in Step 1(9.1 g), toluene(200 ml), and 1,8-diazabicyclo[5.4.0)-7-undecene(8 ml) was stirred under refrux for 7 hours. Ethyl acetate was added to the mixture, which was washed successively with water, dil.HCl, aq. NaCHO3, and water, and dried(MgSO4). The solvent was evaporated to provide the title compound as colorless crystals(6.3 g).
Reaction SMILES: [Na].[C:2]([NH:5][C:6]#[N:7])(=[O:4])[CH3:3].[CH2:8](Cl)[CH:9]=[CH2:10]>S1(CCCC1)(=O)=O>[C:6]([N:5]([CH2:10][CH:9]=[CH2:8])[C:2](=[O:4])[CH3:3])#[N:7]
Reactant: C=CCCl
Reactant: CC(=O)NC#N
Agent: [Na]
Solvent: O=S1(=O)CCCC1
Product: C=CCN(C#N)C(C)=O

Procedure:
159.1 g (1.5 mols) of the sodium salt of acetylcyanamide and 137.8 g (1.5 mols +20% excess) of allyl chloride are reacted in 400 ml of sulfolane for 9 hours and 45 minutes at 70°-127° C. analogously to Example 1, and the mixture is worked up in accordance with Example 1. This gives 121.7 g (65.4% of theory) of a colourless distillate, boiling at 98° C./43 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:10][CH2:11][CH2:12][CH2:13][N:14]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[N:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=3[Cl:49])=[CH:34][CH:33]=2)[CH2:15][CH2:16][CH2:17][C:18](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:19])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:71]1[C:75]2=[C:76]3[C:80](=[CH:81][CH:82]=[C:74]2[NH:73][CH:72]=1)[NH:79][CH:78]([C:83]([O:85][CH3:86])=[O:84])[CH2:77]3>CN(C=O)C>[CH3:63][O:62][C:59]1[CH:60]=[CH:61][C:56]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:10][CH2:11][CH2:12][CH2:13][N:14]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[N:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=3[Cl:49])=[CH:34][CH:33]=2)[CH2:15][CH2:16][CH2:17][C:18]([N:73]2[C:74]3[C:75](=[C:76]4[C:80](=[CH:81][CH:82]=3)[NH:79][CH:78]([C:83]([O:85][CH3:86])=[O:84])[CH2:77]4)[CH:71]=[CH:72]2)=[O:19])=[CH:57][CH:58]=1
Reactant: COc1ccc(C(OCCCN(CCCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: COC(=O)C1Cc2c(ccc3[nH]ccc23)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2c(ccc3c2ccn3C(=O)CCCN(CCCOC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)N1
Reaction time: 0.25 h

Procedure:
To a solution of 22 (3.0 g, 3.37 mmol) in 15 mL anhydrous DMF is added triethylamine (0.75 mL) followed by methyl pyrrolo[4,5-e]indoline-7-carboxylate (Boger, D. L., Coleman, R. S., Invergo, B. J. (1987) J. Org. Chem. 52, 1521.) (0.8 g, 3.7 mmol). The resultant solution is stored at room temperature for 20 h. The reaction is analyzed by HPLC to confirm its completeness. DMF is removed on a rotary evaporator equipped with an oil pump. The residue, dark syrup is suspended in 50% ethylacetate/hexanes (˜25 mL). The mixture is sonicated to initiate the crystallization. The crystals are stirred for 15 min, collected by filtration on a sintered glass funnel, washed with methanol (2×30 mL) and dried under vacuum. The yield of the desired product is 2.7 g (87%) as a deep-purple solid. 1H NMR (DMSO-d6) δ: 11.93 (d, J=1.7 Hz, indole NH, 1H), 8.43 (d, J=2.5 Hz, aromatic proton, 1H), 8.3-8.2 (m, aromatic protons, 2H), 7.85-7.75 (m, aromatic protons, 3H), 7.45-7.18 (m, aromatic protons, 10 H), 7.05 (d, J=1.8 Hz, aromatic proton, 1H), 6.97 (d, J=9 Hz, aromatic protons, 2H), 6.87 (d, J=9 Hz, aromatic protons, 4H), 4.12 (t, J=8 Hz, aliphatic protons, 2H), 3.87 (s, ester CH3, 3H), 3.71 (s, CH3, 6H), 3.60 (br t, aliphatic protons, 2H), 3.45 (br t, aliphatic protons, 2H), 3.29 (br t, aliphatic protons, 2H), 3.08 (t, J=5 Hz, aliphatic protons, 2H), 2.5 (br t, obscured by DMSO signal, aliphatic protons, 2H), 1.88 (br m, aliphatic protons, 4H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:35])[N:24]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:25][CH:26]([OH:29])[CH2:27][OH:28])[CH:20]=[C:19]([Cl:36])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:36][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34]1)[CH2:25][CH:26]([OH:29])[CH2:27][OH:28])=[O:35]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CC(O)CO)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CC(O)CO)C1CCCC1
Reaction time: 1 h

Procedure:
A solution of crude (2-{3-chloro-5-[cyclopentyl-(2,3-dihydroxy-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.044 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.007 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])[CH:3]=[CH2:4].[H][H]>O1CCCC1.[Pd]>[ClH:1].[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][CH2:2][CH2:3][CH3:4])[CH2:19][CH2:20]1
Reactant: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1

Procedure:
37.6 Grams of 3-allylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoic acid-hydrochloride (0.1 mole), prepared according to Example 32, were dissolved in 0.3 l of tetrahydrofurane and were hydrogentated in the presence of palladium black at 30° C. and at 40 atmospheres until no more hydrogen was absorbed. Subsequently the catalyst was separated, the solution was evaporated, and the residue was recrystallized from water.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]3[C:7]=2[NH:6][CH:5]=[CH:4]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1ccc(F)c2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2ccc(F)c3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 4-fluoro-1H-indole-7-carboxylic acid and 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 113 mg (81%) product as a colorless viscous oil. MS (ISP) 463.4 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:11](=S)=[S:12]>CCO>[O:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:11]1=[S:12]
Reactant: S=C=S
Reactant: Nc1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2ncccc2o1
Temperature: 25 °C
Yield: 91 %

Procedure:
3-Hydroxy-2-aminopyridine (2.00 g, 18.2 mmol) and potassium hydroxide (1.22 g, 21.8 mmol) were dissolved in carbon disulfide (15 mL) and EtOH (25 mL), and the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was suspended in 1 M aqueous HCl, collected by filtration, washed with water (2×) and air-dried. Further drying in a 35° C. vacuum oven gave 2.52 g (91%) of the title compound as a tan solid. LC-MS: RT=4.82 min., [M+H]+=153.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH3:31])([CH3:30])[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)O)[N:12]=1.O.[OH-].[Li+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:32]([CH3:34])[CH3:33])=[C:11]([CH2:13][CH:14]=[CH:15][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]([CH3:30])([CH3:31])[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[N:12]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(O)CCc2nc(-c3ccccc3Cl)oc2C(C)C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC=Cc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
The resulting propionic acid derivative (25 mg, 0.053 mmol) was dissolved in a mixture of ethanol (2 mL) and water (1 mL). To the solution was then added lithium hydroxide monohydrate (6 mg). The mixture was stirred for 20 hours at room temperature, and after cooling with ice, cooled with ice, neutralized by addition of diluted hydrochloric acid, and then subjected to extraction using ethyl acetate. The organic layer was collected, washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was distilled off under reduced pressure, to give 15 mg of the desired compound as colorless oil residue (yield 63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)(=[O:34])=[O:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1OC

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-dimethoxybenzenesulfonyl chloride: ESMS m/e: 504.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([S:8]([CH3:9])=[O:31])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (1.71 g, 5 mmol) in CH2Cl2 (60 mL) was added m-CPBA (1.17 g, 5.2 mmol). The mixture was stirred at room temperature for 10 minutes, then directly loaded onto a column. Flash chromatography (mobile phase EtOAc/Hexane) afforded the title compound as a white solid 1.58 g (88%). LC-MS m/z 358 (M+H)+.