Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][N:17](COCC[Si](C)(C)C)[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>CO>[OH:1][CH:2]1[CH2:5][C:4]([CH2:28][C:29]#[N:30])([N:6]2[CH:10]=[C:9]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH:8]=[N:7]2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(O)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: CO
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CC(O)C1

Procedure:
3-Hydroxy-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.020 g, 0.000046 mol) was treated with trifluoroacetic acid (0.5 mL, 0.006 mol) at rt for 30 min and evaporated to dry. The resultant residue was mixed with ethylenediamine (0.2 mL, 0.003 mol) in MeOH (1 mL) for 2 h. The reaction was concentrated and purified on prep. LCMS (pH=10) to give 2 isomers of the desired products. First peak retention time 0.714 min, LCMS calculated for C15H15N6O(M+H)+: 295.1; Found: 295.3. Second peak retention time 0.750 min, LCMS calculated for C15H15N6O(M+H)+: 295.1; Found: 295.3. 1H NMR (400 MHz, CD3OD): δ 8.67 (1H, s), 8.66 (1H, s), 8.38 (1H, s), 7.51 (1H, d, J=3.6 Hz), 6.98 (1H, d, J=3.6 Hz), 4.37 (1H, s), 3.34 (2H, s), 3.22 (2H, m), 2.48 (2H, m) ppm.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[NH:25][C:23](=[O:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].[C:31]1([N:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:30]2[N:29]=[C:26]([NH:27][CH3:28])[N:25]=[C:23]([O:24][C:38](=[O:39])[N:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CNc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c(=O)[nH]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CNc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2′,3′,5′-tri-O-acetyl-2-N-methylguanosine 3 (3.0 g, 7.1 mmol, 1.0 eq) in dry pyridine (50 mL) were added diphenylcarbamoyl chloride (3.45 g, 15 mmol, 2.1 eq) and diisopropylethylamine (1.9 mL, 11.4 mmol, 1.6 eq). The dark brown reaction mixture was then stirred at room temperature for 1 h to obtain 2′,3′,5′-tri-O-acetyl-6-O-(diphenylcarbamoyl)-2-N-methylguanosine 4. TLC showed complete conversion at this stage of the reaction. The reaction mixture was then diluted with pyridine (15 mL) and EtOH (30 mL). To this solution cooled at 0° C. was added 2 M NaOH (25 mL), which was precooled at 0° C. The reaction mixture was stirred for 10 min at 0° C. Acetic acid (c.a. 5 mL) was then added to neutralize the solution. Extraction with CH2Cl2 followed by chromatography on silica gel afforded 5 in 55% yield (1.92 g). TLC (CH2Cl2:MeOH, 9:1 v/v): Rf=0.5; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 2.81 (d, 3H), 3.51-3.56 (m, 1H), 3.61-3.66 (m, 1H), 3.90 (m, 1H), 4.02 (q, 1H), 4.15 (br.d, 1H), 4.62 (br.s, 1H), 4.99 (br.s, 1H), 5.21 (d, J=4.8 Hz, 1H), 5.48 (d, J=5.6 Hz, 1H), 5.82 (d, J=5.6 Hz, 1H), 7.28-7.32 (m, 4H), 7.4-7.44 (m, 6H), 8.19 (s, 1H); 13C NMR (DMSO-d6, 400 MHz) δ (ppm): 28.3, 61.5, 70.5, 73.1, 85.5, 116.4, 127.1, 129.4, 140.9, 141.8, 150.4, 155.6, 155.9, 159.6; ESI-MS (ES+) calculated for C24H24N6O6 492.1757, found 493.2 (M+H+), 515.2 (2M+Na+), 1007.4 (2M+Na+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32](O)=[O:33])=[CH:4][N:3]=1.[CH3:35][O:36][CH:37]([O:40][CH3:41])[CH2:38][NH2:39].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:39][CH2:38][CH:37]([O:40][CH3:41])[O:36][CH3:35])=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: COC(CN)OC
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COc1cc(-c2csc3c(C(=O)NCC(OC)OC)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxylic acid (1.0 g, 2.1 mmol) and 2,2-dimethoxy-1-ethanamine (252 uL, 2.3 mmol) were reacted according to General Procedure D. MP-carbonate resin (5 g) was added, and the mixture was shaken for 2 hours. The resin was filtered from the mixture and the filtrate was concentrated in vacuo to yield 1.5 g crude material. Isopropyl alcohol (35 mL) was added and the crude product was triturated and filtered to yield the title compound (830 mg, 71% yield): 1H NMR (DMSO, 400 MHz) δ 9.48 (s, 1H), 8.56 (s, 2H), 7.98 (d, 1H), 7.69 (d, 1H), 7.56-7.58 (m, 2H), 7.31-7.33 (m, 2H), 7.04-7.17 (m, 3H), 4.54 (t, 1H), 4.02 (s, 3H), 3.89 (s, 3H), 3.37 (t, 2H), 3.31 (s, 6H), 2.51 (t, 2H); RP-HPLC (Conditions j) Rt 12.2 min. MS: 560.0 MH+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[C:21]([C:26]1[O:27][C:28]2[C:33]([C:34](=[O:44])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[C:32]([OH:45])[CH:31]=[C:30]([OH:46])[CH:29]=2)([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:21]([C:26]1[O:27][C:28]2[CH:29]=[C:30]([O:46][CH2:2][C:3]3[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]4[CH:18]=[CH:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)=[CH:5][CH:4]=3)[CH:31]=[C:32]([OH:45])[C:33]=2[C:34](=[O:44])[C:35]=1[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(OC)cc1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1oc2cc(OCc3ccc(OCc4ccc5ccccc5n4)cc3)cc(O)c2c(=O)c1-c1ccc(OC)cc1

Procedure:
0.62 g of 2-(4-chloromethylphenoxy)methyl quinoline, 0.78 g of 2-carboethoxy-5,7-dihydroxy-4'-methoxy isoflavone and 0.31 g potassium carbonate are refluxed in 30 ml of acetone for 17 hours. The mixture was concentrated and the crude product purified by flash chromatography on silica gel and crystallized from toluene to give 2-carboethoxy-5-hydroxy-3-(4-methoxyphenyl)-7-(4-(quinolin-2- ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([O:19][CH3:20])[CH:11]=1>CCCCCCC.C(OCC)(=O)C.CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[C:3]([NH2:8])=[CH:4][N:5]=[N:6][CH:7]=2)=[C:12]([O:19][CH3:20])[CH:11]=1
Reactant: Nc1cnncc1Cl
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)ccc1-c1cnncc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 5-chloro-pyridazin-4-ylamine (CAS RN 53180-92-0) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:ethyl acetate:methanol (100:0:0 to 0:100:0 to 0:50:50) for the chromatographic purification. Light yellow solid (37%). MS (ESI+): m/z=220.089 ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Cl)[CH3:25].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:30])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reactant: CCOC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(c2cc3c(cc2Cl)c(=O)c(C(=O)O)cn3CC)CC1
Yield: 49.8 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydoquinoline-3-carboxylic acid 1.7 g (0.01 mole), ethylchloroacetate 1.2 g (0.01 mole), triethylamine 1.0 g (0.01 mole) and DMF 10 ml was heated at 90°-100° C. for 3 hours under stirring. The reaction mixture was cooled, evaporated under vacuum, the residue was dissolved in dichloromethane, washed with water, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 2.1 g (quantitative) of 1-ethyl-6-chloro-7-(4-ethoxycarbonylmethyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless powders.
Reaction SMILES: [Mg].C(I)C.[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7].[CH2:22]=[O:23].[NH4+].[Cl-]>C1COCC1>[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:22][OH:23])=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7]
Reactant: C=O
Reactant: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: C=CCc1c([SiH](C)C)cc(CO)c2ccccc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a vigorously stirred suspension of activated magnesium turning (480 mg, 20 mmol) in dry THF (70 mL) were added a piece of 12 and ethyl iodide (50 μL). The reaction mixture was heated to reflux until the red color disappeared. Heating (65° C.) of the suspension was continued while a solution of 1-allyldimethylsilyl-4-bromo-naphthalene (1 Scheme 26, 3.0 g, 10 mmol) in THF (20 mL) was added over a period of 15 min. Upon completion of the addition, the gray solution was heated further for 10 min and transferred to a separate flask containing. paraformaldehyde (700 mg) in THF (20 mL) via cannula. After stirring the reaction mixture at 50° C. for 30 min, concentrated NH4Cl (10 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (70 mL) and brine (30 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a colorless oil (1.8 g, 75%); 1H NMR (300 MHz, CDCl3) δ 0.58 (s, 6 H), 2.08 (d, J=7.50 Hz, 2 H), 3.21 (s, OH, 1 H), 4.93-5.03 (2 H), 5.04 (s, 2 H), 5.89 (m, 1 H), 7.47 (d, J=7.20 Hz, 2 H), 7.53-7.64 (2 H), 7.69 (d, J=6.90 Hz, 1 H), 8.11 (d, J=8.80 Hz, 1 H), 8.23 (d, J=8.80 Hz, 1 H), 13C NMR (75 MHz, CDCl3) −1.50 (2 C), 24.6, 63.5, 114.1, 124.5, 124.8, 125.9, 126.8, 129.1, 131.4, 133.7, 135.0, 137.3, 137.5, 138.3.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5](=[N:24][C:25]1[CH:36]=[CH:35][C:28]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[CH:27][CH:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)[CH:7]=1.O>COCOC.COCCOC>[CH3:1][S:2][C:5](=[N:24][C:25]1[CH:36]=[CH:35][C:28]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])=[CH:27][CH:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)[CH:7]=1
Reactant: C=CCOC(=O)c1ccc(N=C(Cl)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: COCOC
Product: C=CCOC(=O)c1ccc(N=C(SC)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1

Procedure:
In a round bottom flask, 700 mg (10 mmoles) of sodium thiomethylate are suspended in 25 ml of dimethoxymethane. At ambient temperature and under a nitrogen stream, there are slowly introduced 3.5 g (7.6 mmoles) of allyl 4-[α-chloro-3-(1-adamantyl)-4-methoxybenzylideneamino]benzoate obtained in Example 4(b) and dissolved in 50 ml of DME. After 3 hours of reaction, the mixture is poured into water and extracted with ethyl ether. The organic phase is dried on sodium sulfate, then evaporated under a vacuum; the resulting crude product is chromatographed on a silica column eluted with a 20/80 mixture of ethyl ether and hexane. After evaporation of the solvents 2.6 g (73%) of the expected product whose melting point is 50°-53° C. are obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[C:38]([N+:45]([O-:47])=[O:46])=[CH:37][C:33]=1[C:34](O)=[O:35].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>C(Cl)Cl.CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([N+:45]([O-:47])=[O:46])[C:39]([NH:41][C:42](=[O:44])[CH3:43])=[CH:40][C:32]=2[O:31][CH3:30])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (4.12 g; 0.02 moles) and 1-benzyl-4-aminopiperidine (3.8 g; 0.02 moles) were added successively to a solution of 2-methoxy-4-acetamido-5-nitrobenzoic acid (5.1 g; 0.02 moles) in methylene chloride (125 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give a solid. It was suspended in hot methanol and treated with the stoichiometric amount of fumaric acid to give a solution from which the N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-nitrobenzamide fumarate (6.2 g) crystallized. After recrystallization from methanol this compound melted at 204°-206° C.
Reaction SMILES: OC(CO)CN(CC(O)CO)CCCN.OC(CO)CN(CC(O)CO)CCCN(CC(O)CO)CCCN.[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][CH2:48][CH:49]([NH:59][CH2:60][CH2:61][CH2:62][N:63]([CH2:78][CH:79]([OH:82])[CH2:80][OH:81])[CH2:64][CH2:65][CH2:66][N:67](CC(O)CO)CC(O)CO)[CH2:50][CH2:51][CH:52]1[CH2:57][CH:56]2[CH2:58][CH:53]1[CH2:54][CH2:55]2>>[CH:40]12[CH2:46][CH:43]([CH2:44][CH2:45]1)[CH2:42][CH:41]2[CH2:47][CH2:48][CH:49]([NH:59][CH2:60][CH2:61][CH2:62][N:63]([CH2:78][CH:79]([OH:82])[CH2:80][OH:81])[CH2:64][CH2:65][CH2:66][NH2:67])[CH2:50][CH2:51][CH:52]1[CH2:57][CH:56]2[CH2:58][CH:53]1[CH2:54][CH2:55]2
Reactant: OCC(O)CN(CCCNC(CCC1CC2CCC1C2)CCC1CC2CCC1C2)CCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CCCN(CC(O)CO)CC(O)CO)CC(O)CO
Product: NCCCN(CCCNC(CCC1CC2CCC1C2)CCC1CC2CCC1C2)CC(O)CO

Procedure:
In a like manner and using analogous quantities, but employing N,N-di-(2,3-dihydroxypropyl)trimethylenediamine and 1,1,5-tri-(2,3-dihydroxypropyl)-1,5,9 -triazanonane instead of 3,3'-(2,3-dihydroxypropylimino)bispropylamine there are prepared respectively N-[1,5-di-2-norbornyl)-3 -pentyl]-N'-di-(2,3-dihydroxypropyl)trimethylenediamine, and 1-[1,5-di-(2-norbornyl)-3-pentyl]5-(2,3-dihydroxypropyl)-9,9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=12.C(Cl)(=O)C(Cl)=O.[O:20]1[CH2:23][CH:22]([NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=2)[CH2:21]1.[H-].[Na+]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]([N:24]([C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][N:26]=3)[CH:22]3[CH2:21][O:20][CH2:23]3)=[O:13])=[CH:7][C:6]=12
Reactant: O=C(O)c1ccn2ncc(Br)c2c1
Reactant: N#Cc1ccc(NC2COC2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(C(=O)c2ccn3ncc(Br)c3c2)C2COC2)nc1
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a solution of 3-bromopyrazolo[1,5-a]pyridine-5-carboxylic acid (I-7, 240 mg, 1 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.25 mL) and catalytic amounts of anhydrous dimethylformamide at rt. The reaction mixture was stirred for 30 minutes and subsequently the solvent was removed under reduced pressure. To the residual acid chloride was added a solution of 6-(oxetan-3-ylamino)nicotinonitrile (I-25, 175 mg, 1 mmol) in dichloromethane (10 mL). The resulting reaction mixture was quickly transferred to a microwave vial and NaH (60% in mineral oil) (191 mg, 5 mmol) was added. The vial was heatedin a microwave oven at 80° C. for 3 h. The reaction mixture was diluted with dichloromethane (15 mL) and subsequently washed with water, sat. NaHCO3 solution and brine. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (chloroform/MeOH, 0-10% EtOAc) to afford 75 mg (20%) of 3-bromo-N-(5-cyanopyridin-2-yl)-N-(oxetan-3-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (I-26) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.0 Hz, 1H), 8.16 (s, 1H), 8.02 (t, J=7.90 Hz, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.33-7.31 (m, 1H), 6.90-6.87 (m, 1H), 6.43 (d, J=10.1 Hz, 1H), 4.67-4.62 (m, 1H), 4.52-4.43 (m, 2H), 4.25-4.19 (m, 1H), 4.03-3.98 (m, 1H); ESI-LC/MS (m/z): [M+H]+ 398.13, [(M+2)+H]+ 400.08, RT 1.25 min.
Reaction SMILES: [CH3:1][Li].[C:3]1([C:17]([OH:19])=O)[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.N#N.Cl>O1CCCC1.O>[C:3]1([C:17](=[O:19])[CH3:1])[C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc2c1Sc1ccccc1S2
Reactant: [Li]C
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc2c1Sc1ccccc1S2
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
Methyl lithium (1.6M in ether, 57 ml, 90 mmol) was added drop wise to a stirred solution of thianthrene-1-carboxylic acid (11.71 g, 45 mmol) in dry tetrahydrofuran (200 ml) at −78° C. over 30 minutes under an inert atmosphere (N2). The reaction mixture was allowed to warm to room temperature and (very thick white suspension present) was left stirring for 4 hours. Water (10 ml) was then added carefully to the solution and the pH was adjusted to 1 (pH paper) with 2N HCl. The solvent was removed in vacuo and the yellow solid formed was filtered and dried overnight in a vacuum desiccators. The solid was then purified by column chromatography (ethyl acetate/hexane; 1:9) and was recrystalised from ethanol to give the desired product (6.58 g, 57%). 1HNMR (300 MHz, CDCl3): δH=2.65 (3H, s); 7.26 (3H, m); 7.47 (2H, m); 7.62 (2H, d). m/z (LC-MS, ESP) RT=4.95 min; (M++1)=259
Reaction SMILES: C(O[NH:6][C:7](=C=O)[C:8](O)=[O:9])(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:24]([O:31][C:32](=[O:36])[C@@H:33]([CH3:35])[NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:60]>>[ClH:60].[CH2:24]([O:31][C:32](=[O:36])[C@@H:33]([CH3:35])[NH:34][C:8](=[O:9])[CH2:7][NH2:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)ONC(=C=O)C(=O)O
Reactant: ClCCl
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)CN)C(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a cold (0° C.) solution of 100 ml. methylene chloride containing 10 g. (57 mmol) of N-t-butyloxy-carbonylglycine, 20 g. (57 mmol) of D-alanine benzyl ester p-toluene sulfonic acid salt and 5.77 g. (57 mmol) of triethylamine was added 12.3 g. (60 mmol) of dicyclohexylcarbodiimide and the resulting reaction mixture allowed to warm to room temperature. After 18 hours the mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in 200 ml. of ethyl acetate and the organic layer washed with 2.5% hydrochloric acid, water, a saturated sodium bicarbonate solution and a brine solution. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. To the resulting oil 200 ml. of dioxane saturated with hydrogen chloride was added. After 30 minutes 400 ml. of diethyl ether was added and the product filtered under nitrogen, 10.9 g. (70% yield).
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:26]1[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=1)=[C:6]([CH:24]=[O:25])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:14]=1)C.NC1C=CC=CC=1S.Cl.[CH3:44][CH2:45][OH:46]>>[CH2:45]([O:46][C:24]([C:6]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)[CH:14]=2)[C:8]2[C:4]([C:5]=1[C:26]1[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=1)=[CH:3][CH:11]=[CH:10][CH:9]=2)=[O:25])[CH3:44]
Reactant: CCO
Reactant: CCc1cccc2c1c(-c1nc3ccccc3s1)c(C=O)n2Cc1cccc(OCC2CC2)c1
Agent: Cl
Agent: Nc1ccccc1S
Product: CCOC(=O)c1c(-c2nc3ccccc3s2)c2ccccc2n1Cc1cccc(OCC2CC2)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Ethyl-3-benzthiazol-2-yl-1-(3-cyclopropylmethoxybenzyl)-1H-indole-2-carboxaldehyde (Example 41, 0.42 g, 1.1 mmol) was taken up in EtOH (30 mL) at room temperature. 2-aminothiophenol (0.15 g, 1.05 eq.) was added, followed by conc. HCl (0.5 mL), and the reaction mixture was heated to reflux for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (3×50 mL.) The organic layers were separated, dried over sodium sulfate, and concentrated in vacuo to give the desired product (0.38 g, 71%) which was taken to the hydrolysis step without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[S:51][CH:52]=[C:53]([CH3:55])[N:54]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[S:51][CH:52]=[C:53]([CH3:55])[N:54]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: Cc1csc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 45.3 %

Procedure:
A solution of triphenylphosphine (238 mg, 0.91 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (183 mg, 1.03 mmol). The reaction mixture was stirred at 0° C. until it became homogeneous. The resulting light purple reaction mixture was then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 137, 200 mg, 0.61 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-4-methylthiazole (104 mg, 0.91 mmol) and pyridine (0.15 mL, 1.82 mmol), and the resulting reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 70/30 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide (118 mg, 46%) as an off-white foam: [α]23589=−44.4° (c=0.024, chloroform); EI-HRMS m/e calcd for C19H23ClN2O3S2 (M+) 426.0838, found 426.0837.