Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:4]3[CH2:3][C@@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:11][C:12]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:23][CH2:22]1
Reactant: C[C@@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 4.6 %

Procedure:
Using (R)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 7 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 1, the title compound (23 mg) was obtained.
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1.[H-].[Na+].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[CH2:39][N:38]([C:41]1[S:42][C:43]([CH2:51][CH2:52][CH2:53]I)=[C:44]([C:46]([O:48]CC)=[O:47])[N:45]=1)[CH2:37][CH2:36]2)=[O:30].[OH-].[Na+]>CN(C=O)C.CO.C1COCC1>[N:1]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:53][CH2:52][CH2:51][C:43]3[S:42][C:41]([N:38]4[CH2:37][CH2:36][C:35]5[C:40](=[C:31]([C:29](=[O:30])[NH:28][C:20]6[S:19][C:23]7[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=7[N:21]=6)[CH:32]=[CH:33][CH:34]=5)[CH2:39]4)=[N:45][C:44]=3[C:46]([OH:48])=[O:47])=[CH:14][CH:15]=2)[C:5]2=[N:6][CH:7]=[N:8][CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: Oc1ccc(-n2ncc3cncnc32)cc1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCOc3ccc(-n4ncc5cncnc54)cc3)s1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 21D (106 mg, 0.498 mmol) in DMF (5 mL) was added sodium hydride (56.9 mg, 1.423 mmol). The resulting mixture was stirred at rt for 30 minutes and compound 2C (300 mg, 0.474 mmol) was added. The reaction mixture was stirred for 1 hour and 10% sodium hydroxide (1.897 mL, 4.74 mmol), THF (5 mL) and MeOH (3 mL) was added. The resulting mixture was stirred at 70° C. overnight, cooled, and filtered. The filtrate was acidified by HCl to pH 4. The precipitate was collected and dried to provide the desired product: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.85 (1H, s), 9.45 (1H, s), 9.10 (1H, s), 8.61 (1H, s), 7.98-8.06 (3H, m), 7.78 (1H, d), 7.67 (1H, d), 7.42-7.50 (2H, m), 7.32-7.40 (2H, m), 7.09-7.16 (2H, m), 4.84 (2H, s), 4.06 (2H, t), 3.73 (2H, t), 3.14-3.24 (2H, m), 3.03 (2H, t), 1.98-2.12 (2H, m); LCMS (APCI): m/z 687 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][O:21][CH3:22]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:23])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: COCCOC(=O)Cl
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Solvent: CCOC(C)=O
Product: COCCOC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 10.00 g (35.44 mmol) of 3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine dissolved in 120 mL of EtOAc, at 0° C. was added 5.40 g (38.99 mmol) of 2-methoxyethyl carbonochloridate, followed by 9.86 mL (70.88 mmol) of TEA. After 5 minutes, the ice bath was removed, and the reaction mixture stirred at RT. After 5 hr, LCMS showed that the reaction was complete. It was diluted with EtOAc, quenched with brine, and the organic layer dried over MgSO4. It was concentrated and purified on the ISCO with a 330 g column eluting with 0-9% MeOH/DCM to obtain the desired product, 12.63 g (93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.42 (s, 3 H) 3.62-3.69 (m, 6 H) 3.73-3.82 (m, 4 H) 4.26-4.35 (m, 2 H) 6.36 (d, J=7.83 Hz, 1 H) 7.86 (s, 1 H) 8.27 (d, J=7.83 Hz, 1 H). LRMS (ESI) m/e 384 [(M+H)+, (doublet), calcd for C14H18BrN5O3 383].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.CCN(C(C)C)C(C)C.[NH2:57][C@H:58]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:59][CH2:60][C:61](=[O:63])[OH:62]>C1COCC1.CN1C(=O)CCC1>[C:67]([O:66][C:64](=[O:65])[C@@H:58]([NH:57][C:25](=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:12][CH:11]=1)[CH2:59][CH2:60][C:61]([OH:63])=[O:62])([CH3:70])([CH3:68])[CH3:69]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)O)s1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(12-carboxydodecyl)-thiophene-2-carboxylic acid tert-butyl ester (31 mg, 0.0 78 mmol) was treated with TSTU (28.2 mg, 0.094 mmol) and DIPEA (0.016 mL, 0.094 mmol) in THF (1.3 mL) for 2½ hours at room temperature under nitrogen. The solvent was removed in vacuo and the mixture added NMP (1 mL) and H-Glu-OtBu (31.3 mg, 0.154 mmol) and DIPEA (0.027 mL). The mixture was stirred overnight at room temperature. The mixture was separated between diethyl ether (10 mL) and 10% aqueous NaHSO4 (2×10 mL) and the organic phase isolated and solvent removed in vacuo to give the crude (S)-2-[13-(5-tert-Butoxycarbonylthiophen-2-yl)-tridecanoylamino]-pentanedioic acid 1-tert-butyl ester which was subsequently in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20].[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CCOCC.C1COCC1>[N:28]1[CH:29]=[CH:30][C:25]([NH:24][C:18](=[O:22])[C:19]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[CH:8]=2)=[O:20])=[CH:26][CH:27]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Fc1ccc(Cn2ccc3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1ccncc1)C(=O)c1cn(Cc2ccc(F)cc2)c2ccccc12
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A solution of 4.75 g (21.1 mmol) of 1-(4-fluorobenzyl)indole in 25 ml of ether is added dropwise at 0° C. and under N2 to a solution of 2.25 ml of oxalyl chloride in 25 ml of ether. The mixture is refluxed for 2 hours and the solvent is then evaporated. 50 ml of tetrahydrofuran were then added to the residue, and the solution is cooled to −5° C. and treated dropwise with a solution of 4.66 g (49.5 mmol) of 4-aminopyridine in 200 ml of THF. The mixture is refluxed for 3 hours and allowed to stand at room temperature overnight. The 4-aminopyridine hydrochloride is filtered off with suction, the precipitate is washed with THF, the filtrate is concentrated in vacuo and the residue is recrystallized from ethyl acetate.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:33])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1>CO.O>[F:33][C:5]([F:4])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
Lithium hydroxide monohydrate (0.373 g, 8.90 mmol) was added to ethyl 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoate (3.40 g, 8.09 mmol) in a mixture of MeOH (60 mL) and water (30 mL). The resulting suspension was stirred at 50° C. for 16 hours. Further lithium hydroxide monohydrate (0.373 g, 8.90 mmol) was added, the temperature was increased to 65° C. and the suspension was stirred for a further 6 hours. The reaction mixture was cooled to room temperature and the MeOH evaporated. The residues were dissolved in water (200 mL) and filtered. The filtrate was acidified with 1M citric acid until precipitation ceased, and the precipitate was collected by filtration, washed with water and dried under vacuum to afford 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]benzoic acid (3.17 g, 100%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:23])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)CCC>[C:24]1([C@H:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:10]4[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:8][CH:9]=4)[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCl)cc3)cc12)c1ccccc1
Reactant: C1CCNCC1
Solvent: CCCCO
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CN4CCCCC4)cc3)cc12)c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 80 mg (0.19 mmol) 2-chloro-N-{4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide in 1.5 ml n-butanol is treated with 47 μl (0.48 mmol) piperidine and then heated to 100° C. for 2 h. The clear solution is cooled and the solvent evaporated. The residue is purified with flash chromatography using a mixture of ethyl acetate/methanol with increasing concentrations of methanol starting with 100:2.5 and ending with 10:1. The title compound is obtained as a colorless powder; m.p. 194-196° C.; MS-ES+: (M+H)+=469.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.O.C1C[O:40][CH2:39]C1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[CH2:25][C:26]4[O:27][C:39](=[O:40])[NH:29][N:28]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(CC(=O)NN)c4)c23)cc1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(Cc5n[nH]c(=O)o5)c4)c23)cc1
Temperature: 25 °C

Procedure:
Heat 0.85 mg (0.183 mmol) of 2-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acetic hydrazide and 35.5 mg (0.219 mmol) of N,N′-carbonyldiimidazole under reflux in 3 ml of THF for 2 h. After cooling to RT, add to water and extract repeatedly with dichloromethane. Dry the combined organic phases over magnesium sulphate and concentrate under reduced pressure. 79.9 mg (89% of theory) of the target product are obtained as a beige solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]2[CH2:16][C:15](=[O:17])[NH:14][S:13]2(=[O:19])=[O:18])[CH:7]=1>O.CO>[O:19]=[S:13]1(=[O:18])[NH:14][C:15](=[O:17])[CH2:16][N:12]1[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:20])=[O:4]
Reactant: COC(=O)c1cccc(N2CC(=O)NS2(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CN(c2cccc(C(=O)O)c2)S(=O)(=O)N1

Procedure:
A solution of sodium hydroxide (105.4 mg, 2.64 mmol) in water (2.54 g) is added to a solution of the Example 37 title compound, 3-(1,1,4-Trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid methyl ester (37.1 mg, 0.137 mmol) in MeOH (5.48 mL). This is allowed to stir 13 h and then neutralized by addition of 1N aqueous HCl (2.64 mL). The reaction mixture is loaded onto a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in two equal aliquots and eluted at 30 mL/min with a gradient of 100:0 (water containing 0.1% TFA: MeCN) for 0 min to 2.5 min, then to 10:90 at 5.5 min. Then held at 10:90 until 7 min. Fractions containing the product are combined and concentrated on a Savant Speedvac to yield 3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzoic acid as a white powder: API-Ms [M−H]=255.09.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[N:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9].[CH3:17][I:18]>CC(C)=O>[IH:18].[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[N:7][C:8]([S:9][CH3:17])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN1CCNC1=NC(=S)Nc1ccccc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=Nc1ccccc1)N=C1NCCN1C
Product: I
Yield: 84.8 %

Procedure:
A mixture of 22.0 g (0.094 mole) of N-(1-methyl-2-imidazolidinylidene)-N'-phenylthiourea and 14.9 g (0.105 mole) of methyliodide in 500 ml of acetone is refluxed for 2.5 hours. The reaction mixture is evaporated in vacuo and the oil obtained is crystallized from acetone-ether (1:1) to give 30 g (85%) of methyl N-(1-methyl-2-imidazolidinylidene)-N'-phenylcarbamimidothioate hydroiodide; m.p. 122°-126° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:6]1=2)=[O:4].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C)C=O>>[CH3:12][C:8]1([CH3:13])[CH2:9][CH2:10][CH2:11][N:5]([C:3](=[O:4])[CH2:2][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:6]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:7]1=2
Reactant: CC1(C)CCCN(C(=O)CCl)c2cc([N+](=O)[O-])ccc21
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CC1(C)CCCN(C(=O)CN2CCCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (0.494 g, 0.00166 mol), pyrrolidine (0.310 mL, 0.00371 mol) and N,N-dimethylformamide (5.0 mL, 0.064 mol) were combined in a round bottom flask and stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with water and then brine. The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with ether to yield a crude orange solid, 1-(5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-pyrrolidin-1-yl-ethanone. LCMS: m/z=332.33 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11]2(OCC[O:14]2)[CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.O.Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH3:13])=[N:5][N:4]=[N:3]1
Reactant: CCC1(CCCSc2nnnn2C)OCCO1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)CCCSc1nnnn1C
Yield: 80.4 %

Procedure:
1-Methyl-5-(4,4-ethylenedioxyhexyl)thio-1,2,3,4-tetrazole (0.6 g) is dissolved in acetic acid (5 ml). Water (2.5 ml) and conc. hydrochloric acid (0.5 ml) are added to the solution and the mixture is heated on a water bath for 1 hour. Water is added to the reaction mixture and the mixture is extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Kieselgel 60). The column is eluted with benzene-ether (10:1) to obtain 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.4 g) as colorless liquid, nD25 =1.5042.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:29]2[CH2:31][CH2:30]2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][CH:25]=[N:24][C:23]=3[CH3:27])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[CH:29]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:28])[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[O:26][CH:25]=[N:24][C:23]=3[CH3:27])=[CH:20][CH:21]=2)[CH2:31][CH2:30]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]
Reactant: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-{cyclopropyl-[4-(4-methyl-oxazol-5-yl)-benzoyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (180 mg) and trifluoroacetic acid (20% in dichloromethane) is stirred for 1 h at room temperature. The solvent is evaporated to give the title compound as its trifluoroacetic acid salt. Mass spectrum (ESI+): m/z=326 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (260 mg, 1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in THF (3 mL) at rt, was added dropwise a solution of phenyl chloroformate (170 mg, 1.1 mmol) in THF (2 mL) and the reaction mixture was stirred for a further 15 h. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added to the reaction mixtureand stirring continued for an additional 4 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford crude phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg) which was used without further purification. LC-MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=2[C:26](O)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C>[CH:18]1([O:23][C:24]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][C:25]=2[C:26]([N:5]2[CH2:4][CH2:3][N:2]([C:8]3[CH:9]=[N:10][C:11]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:7][CH2:6]2)=[O:27])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3cnc4ccccc4c3)CC2)c1

Procedure:
Prepared in analogy to example 1.1(b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (example 2.3) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH:15]=O.CSC.O>O1CCCC1.B.Cl>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH3:15]
Reactant: CC(C)Cn1c(N)c(NC=O)c(=O)[nH]c1=S
Agent: B
Agent: Cl
Solvent: CSC
Solvent: O
Solvent: C1CCOC1
Product: CNc1c(N)n(CC(C)C)c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 52.6 %

Procedure:
N-(6-Amino-1-isobutyl-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-formamide (0.25 g, 1.0 mmol) was suspended in dry tetrahydrofuran (5 mL) and borane.dimethylsulphide complex (1M in dichloromethane, 2.5 mL, 2.5 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2.5 h. To the resulting clear yellow solution was added a few drops of 2M hydrochloric acid to eliminate unreacted borane. Water was added and the resulting aqueous solution was extracted with dichloromethane (3×15 mL). The combined organic phase was washed with brine and dried over Na2SO4. The solvent was evaporated off under reduced pressure yielding the title compound (0.12 g, 54% yield). This material was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:37]([O:17][C@@H:16]1[C@@H:15]([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[O:14][CH:11]([O:12][CH3:13])[CH2:10][C@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1C[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound (16.9 g, 40.0 mmol) synthesized in Example 6 (6c) was dissolved in methylene chloride (150 mL) and triethylamine (22 mL, 0.16 mol), benzoyl chloride (14 mL, 0.12 mol) and 4-dimethylaminopyridine (489 mg, 4.00 mmol) were added thereto, followed by stirring of the mixture at room temperature for 18 hours. After water (80 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (100 mL), the organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) to obtain the desired title compound (20.8 g, yield 99%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.C(OCC)(=O)C>[F:13][C:14]([F:28])([F:29])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[CH2:5][C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
A solution of 3-methyl-4-nitrobenzyl chloride (0.27 g), 3,5-bis-(trifluoromethyl)phenylboronic acid (0.45 g), tetrakis(triphenylphosfine)palladium (0.1 g) and sodium carbonate (0.48 g) in water (2 ml) and 1,2-dimethoxyethane (10 ml) was stirred under an argon atmosphere at 85° C. for 2 hours. After cooling, the reaction solution was diluted with ethyl acetate and further stirred for 10 minutes by adding water thereto. After washing the organic layer with a saturated salt solution, it was dried over anhydrous magnesium sulfate. The solution was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain 4-(3,5-bis-trifluoromethyl-benzyl)-2-methyl-nitrobenzene (0.44 g).