Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OC(=O)C)C>[C:20]1([S:26]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2[C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cccc(F)c1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2c(F)cccc2F)nc2ccccc21
Reaction time: 0.08 h
Yield: 83 %

Procedure:
2-(2,6-difluorophenyl)benzimidazole (Example 12) (0.31 g, 1.34 mmol) dissolved in THF (5 mL) was added to NaH (0.10 g, 190 M %). After 5 min, benzenesulfonyl chloride (0.25 mL, 0.35 g, 2.00 mmol, 150 M %) was added. After stirring for 2 h, the reaction was dissolved in ethylacetate, and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and then recrystallized from diethylether/hexane (3:1), to yield white powders of 1-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (0.41 g, (1.10 mmol, 83% yield). M.p. 104-106° C. 1H-NMR (300 MHz, CD2Cl2): δ 8.09 (m, 1H, PhSO2), 7.77 (m, 1H, PhSO2), 7.69 (m, 2H, PhSO2), 7.66-7.53 (m, 2H, H4,7), 7.51-7.39 (m, 4H, PhSO2, H3,5), 7.07 (m, 2H, H3′,5′).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]1
Reactant: CC(=O)NC1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 9 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), 4-acetamidopiperidine (43 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, MeOH, 1:1:0.05) to furnish the title compound as white solid (7 mg, 9%), LC-MS (ESI, 3.5 min) Rt 2.25 min; m/z (ESI) C12H16Cl2N3O requires 288.0665 found [M+H]+ 288.0664; HPLC Rt 5.98 min, 100%.
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:17]2[CH:18]=[C:13]([C:12]([F:20])([F:21])[F:11])[CH:14]=[N:15][C:16]2=[O:19])=[CH:5][CH:6]=1
Reactant: O=c1ncc(C(F)(F)F)c[nH]1
Reactant: ClCOc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(C(F)(F)F)cn1COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 1-chloromethoxy-4-chloro-benzene [see Preparation 11](0.35 mmol) in dichloromethane (1 ml) was added with stirring at room temperature to a solution prepared from 5-trifluoromethyl-pyrimidin-2-one (0.33 mmol) and triethylamine (0.33 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 24 h and then it was stirred at 70° C. for 30 min, the solvent was then distilled off, the residue triturated with water, the residual material extracted with chloroform and the dried (MgSO4) chloroform solution evaporated to yield the product, 60 mg (62%), as a mixture of the N- and O-isomers in the ratio 5:1. The isomers were separated by their different solubilities in ether, the O-isomer being the more soluble. The title compound, the N-isomer had m.p. 98° C. (Found C46.78; H2.88. Calc. for C12H8ClF3N2O3 : C47.30; H2.65) 1H NMR (CDCl3); δ 5.85 (CH2), 6.8-7.4 (Ph), 8.15 (H-4, J4.6 3 Hz) 8.76 (H-6) MS [70 eV; m/z (% rel. int.)]; 177 (100), 150(10), 75(5), IR (KBr); 1690 cm-1 (CO).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22]C(=O)CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:36](Cl)(=[O:48])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:36](=[O:48])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOc1ccc(COC(=O)Cl)cc1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: CCOc1ccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)cc1

Procedure:
4-Ethoxybenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (50 mg, 0.17 mmol) and 4-ethoxybenzyl carbonochloridate (58.5 mg, 0.18 mmol) according to General Procedure H to give 65 mg (81%) of pale yellow solid. Anal. Calcd. for C28H36N4O3 m/z 476.3, found: 477.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (d, J=8.9 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 1H), 7.04 (d, J=8.6 Hz, 1H), 6.95 (d, J=9 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.92 (m, 2H), 3.98 (m, 2H), 3.86 (d, J=6.9 Hz, 1H), 3.75 (d, J=12.5 Hz, 1H), 3.07 (m, 1H), 2.76 (m, 1H), 2.35 (m, 2H), 1.89 (m, 1H), 1.78 (m, 2H), 1.64 (m, 3H), 1.44 (m, 1H), 1.30 (t. J=7 Hz, 3H), 1.17 (m, 4H), 1.02 (m, 1H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][C:13]([F:16])([F:15])[CH3:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].O.[OH-].[Li+]>C1COCC1.O>[C:20]([O:19][C:17]([N:6]1[CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][C:13]([F:15])([F:16])[CH3:14])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: COC(=O)C1CC(CCCC(C)(F)F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(F)(F)CCCC1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 4-(4,4-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (88 mg, 0.21 mmol, 1 equiv) in THF (1.2 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (45 mg, 1.07 mmol, 5 equiv). The reaction mixture was stirred at rt overnight. The THF was removed under vacuum. The residue was diluted with water and washed with ether. The aqueous layer was taken up in ethyl acetate, partitioned with 10% citric acid. The organic layer was washed with water (1×), brine (1×), dried and concentrated to give 4-(4,4-difluoro-pentyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (66 mg, 96%).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)(C)C>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][CH:2]=1)([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCCCc1nc[nH]c1Br
Solvent: CC(C)O
Product: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
Reaction of 5-bromo-4-(4-aminobutyl)imidazole with 1-nitro-2,2-bis-methylthioethylene in the procedure of Example 8(i) yields 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene, m.p. 157°-158°, (from isopropanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=2)[C:15](O)=[O:16])=[CH:5][CH:4]=1.[NH:42]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45]>>[CH2:53]([O:52][C:50](=[O:51])[CH2:49][N:42]([CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:40]=[CH:41][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=1)[CH3:54]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)O)c1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1

Procedure:
3-[3-(4-Methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid was converted to the acid chloride which was treated with diethyl iminodiacetate using the procedure of Example 17 to give N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(4-methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as an oil which exhibited nmr and mass spectra consistent with the structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7])#[N:2]
Reactant: CCc1cc(C(=O)O)cc(C#N)c1OC
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To 3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg), toluene (3.5 mL), N,N-dimethylformamide (0.01 mL) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 14 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (387 mg) as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]2[C:7](=[O:30])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([S:20]([C:23]4[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]2[C:7](=[O:30])/[C:8](=[CH:10]/[C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:22])=[O:21])[CH:12]=3)/[O:9][C:5]=2[C:4]=1[CH2:33][N:34]1[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 11 h
Yield: 35.8 %

Procedure:
A solution of tert-butyl (Z)-4-({6-methoxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 0.0621 mmol) in methylene chloride (2 mL) was added with a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 11 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated to obtain (Z)-6-methoxy-7-(piperazin-1-ylmethyl)-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.0121 g, 35%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH2:18]2)[CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[K+].O.[N:34]#[C:35]Br>CO>[CH2:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[CH2:21][CH2:22][CH2:23][N:17]1[C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:35]([NH2:34])=[N:1]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC1=N[C@@H](CCc2cc(N3CCCc4ccccc4C3)nc3ccccc23)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
To the stirred mixture of (2S)-2-amino-4-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-1-ol (110 mg, 0.3 mmol), potassium acetate (90 mg, 0.91 mmol), methanol (8 mL) and water (2 mL) was added a solution of cyanogen bromide (32.3 mg, 0.3 mmol) in cold methanol (2 mL) at 0° C. After the addition, the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give 40 mg of product as a white solid (yield was 34.5%). MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J=7.2 Hz, 1 H), 7.56-7.43 (m, 3 H), 7.17-7.04 (m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J=8.0 Hz, 2 H), 4.13 (brs, 2 H), 3.87 (t, J=7.2 Hz, 1 H), 3.77 (t, J=7.2 Hz, 1 H), 3.01 (brs, 2 H), 2.94-2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72-1.67 (m, 2 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1>N1CCCCC1.C(O)C>[O:16]=[C:10]1[C:9](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.6 %

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (79 mg, 0.36 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol followed by 0.1% of acetic acid in water and dried to give 30 mg (23%) of the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C=O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.0 g (59.7 mmol) trans-4-tert-Butylcyclohexanecarboxylic acid are dissolved in 400 ml dichloromethane plus a few drops of DMF, 9.09 g (71.6 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:8])[CH3:9])[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnn(C(C)(C)C)c1CBr
Yield: 85.2 %

Procedure:
5-Methyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (30 grams, 0.14 mole) and N-bromosuccinimide (25.4 grams, 0.14 mole) were combined in 100 ml. of carbon tetrachloride. A heating lamp was turned onto the reaction mixture, and the reaction mixture was refluxed for three hours. The reaction mixture was then cooled and filtered to remove the succinimide. The filtrate was washed with water, washed with saturated brine, and dried over sodium sulfate and filter paper. The solvent was then removed in vacuo, providing 34.5 grams of the 5-(bromomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23]([NH:25][NH:26][CH:27]=O)=O>ClCCl>[N:25]1[N:26]=[CH:27][N:1]([C:2]2[CH:22]=[CH:21][C:5]([CH2:6][C:7]3[NH:8][C:9](=[O:20])[C:10]4[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=4[N:12]=3)=[CH:4][CH:3]=2)[CH:23]=1
Reactant: O=CNNC=O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(-n4cnnc4)cc3)nc12
Temperature: 200 °C
Reaction time: 0.92 h
Yield: 34.3 %

Procedure:
A mixture of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (297 mg, 0.0010 mol) and 1,2-diformylhydrazine (101 mg, 0.00115 mol) was heated to 200° C. The resulting melt was then stirred under a nitrogen atmosphere at this temperature for 55 minutes. On cooling, the solid was dissolved in dichloromethane:methanol, pre-absorbed onto silica and purified by flash column chromatography eluting with a solvent gradient of dichloromethane:methanol (99:1 to 96:4 by volume) then dichloromethane:methanol:0.880 aqueous ammonia (90:10:1 by volume). Crystallisation from ethyl acetate/methanol gave the title compound (120 mg), m.p.297-300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.Cl.Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Agent: Cl
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (140 mg, 0.52 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (140 mg, 0.65 mmol) to afford the desired product (68 mg, 34%) as an off-white solid: ESI MS m/z 383 [M+H]+
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:33][CH2:34][CH2:35][C@H:36]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:37]([OH:39])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:33]6[CH2:34][CH2:35][C@H:36]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:37]6=[O:39])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)O
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.3 %

Procedure:
To a suspension of 47 (230 mg, 0.51 mmol, scheme 15) in DCM (5.1 mL) were added (S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (224 mg, 1.03 mmol) and acetic acid (59 μl, 1.03 mmol). After stirring for 20 min at room temperature, NaBH(OAc)3 (326 mg, 1.54 mmol) was added. The reaction mixture was stirred for 16 h, quenched by addition of 1N NaOH, and concentrated. The solid was collected by filtration and purified by Biotage (SNAP 50 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 107 (120 mg, 0.19 mmol, 37% yield). MS (m/z): 633.7 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(O[C:14]([S-])=[S:15])C.[K+]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:14]([SH:15])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(=S)[S-]
Reactant: COc1ccc(O)c(N)c1
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2oc(S)nc2c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of 2-amino-4-methoxy-phenol (20.7 g, 0.15 mol), potassium O-ethylxanthate (26.2 g, 0.16 mol) and anhydrous pyridine was refluxed for two hours before it was cooled to room temperature and ice-cold 1N HCl (600 mL) was added. The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a pale red solid (22.36 g): 1H NMR (CDCl3, 200 MHz): δ=7.20 (m, 1H), 6.78 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [C:1]1([C:7](=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:16].BrBr>C(O)(=O)C>[Br:16][CH:8]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: Br
Reactant: O=C(Cc1ccncc1)c1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(c1ccccc1)C(Br)c1ccncc1
Temperature: 60 °C

Procedure:
To a solution of 36 g (182 mmol) of 1-phenyl-2-pyrid-4-ylethanone in 350 mL of acetic acid are successively added at room temperature 28 ml (210 mmol) of a solution containing 30% by weight of hydrobromic acid in acetic acid and 10.1 ml (197 mmol) of bromine dissolved in 50 mL of acetic acid. The solution is heated at 60° C. for one hour and then cooled. The product is precipitated by adding diethyl ether, and 63 g of a yellow solid are isolated after drying.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]([CH2:15][OH:16])[CH2:13]O)[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH2:5]2.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH:12]1[CH2:15][O:16][CH2:13]1)[O:8][CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[CH2:5]2
Reactant: CCCC1COc2cc(C(CO)CO)c(F)cc2C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1COc2cc(C3COC3)c(F)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.80 g (13.7 mmol) of 2-(6-fluoro-3-propylchroman-7-yl)propane-1,3-diol are dissolved in 70 ml of THF, and 8.7 ml (13.7 mmol) of a 15 percent solution of n-butyllithium in hexane are added at 0° C. After 30 min, 2.7 g (14.2 mmol) of p-toluenesulfonyl chloride in 30 ml of THF are added, and the mixture is stirred at RT for 1 h and re-cooled to 0° C. After addition of a further 8.7 ml (13.7 mmol) of a 15% solution of n-butyllithium in hexane, the cooling is removed, and the batch is heated under reflux for 4 h. The batch is subsequently diluted with MTB ether and washed with water. The org. phase is dried over sodium sulfate and evaporated, and the crude product is purified by chromatography on silica gel with heptane/ethyl acetate (3:2). The product fractions (Rf=0.5) are evaporated, and the product is used without further purification.