Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH3:2].C([BH3-])#N.[Na+].[NH2:8][C:9]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[NH2:30])(=[O:21])=[O:20])[C:10]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>CO.Cl.CC(O)=O>[NH2:8][C:9]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:38])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[NH:30][CH2:1][CH3:2])(=[O:21])=[O:20])[C:10]1=[O:31]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(N)c1
Reactant: CC=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1cc(OC)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.6 ml of AcOH and then 0.09 ml of acetaldehyde and 0.038 g of sodium cyanoborohydride are added at RT to a solution of 0.830 g of the compound obtained in EXAMPLE 106 in 22 ml of MeOH. After stirring for 4 hours at RT, 2 drops of concentrated HCl are added and the reaction mixture is then neutralized by the addition of a 5% solution of potassium carbonate. The solvent is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with a saturated solution of sodium chloride and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/hexane mixture (80/20; v/v) and then DCM as the eluent to give 0.396 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=192°-196° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:46][CH:47]([CH3:49])[CH3:48])[C:22]([NH:24][N:25]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:26][C@H:27]([N:29]1C(=O)C2=CC=CC=C2C1=O)[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/C1C=CC=CC=1)=[O:10].[OH2:50].NN>CO>[NH2:29][C@@H:27]([C:26]([N:25]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12]/[CH:13]=[CH:14]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:50])[CH3:28]
Reactant: O
Reactant: CC(C)C[C@@H](C(=O)NN(C[C@@H](C)N1C(=O)c2ccccc2C1=O)c1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: NN
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(C(=O)[C@@H](C)N)c1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 5.5 h

Procedure:
A solution of 0.22 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-2′-phenyl-2′-(2(R)-phthalimidopropyl)valerohydrazide in 4 ml of methanol was treated with 0.04 g of hydrazine hydrate. The mixture was stirred for 5.5 hours and then the solvent was evaporated. The residue was suspended in 2 ml of dichloromethane and stirred at 4° C. overnight. The suspended solid was filtered off, the filtrate was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (20:1) for the elution. There was obtained 0.189 of (E)-2′-(D-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide in the form of a colorless foam.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15]>O.[OH-].[Na+]>[C:3]([CH2:2][NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=1[C:12]([OH:21])=[O:20])([OH:5])=[O:4]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CNc1ccccc1C(=O)O
Temperature: 42.5 °C
Reaction time: 96 h

Procedure:
To a solution of chloroacetic acid (347 g, 3.67 mol) in water (500 mL), sodium carbonate (200 g, 4.72 mol) was carefully added at room temperature under stirring. The formed solution was heated to 40-45° C. and quickly added to a mixture prepared from a suspension of anthranilic acid (500 g, 3.65 mol) in water (340 mL) and 35% aqueous sodium hydroxide solution (320 mL) and heated to 40-45° C. The reaction mixture was kept at 40° C. for 4 days and the solid reaction mixture was treated with a solution of sodium hydroxide (150 g, 3.75 mol) in water (4 L). The mixture was heated to 60° C. and filtered off while hot. The solid residue was washed on the filter with 20% aqueous sodium hydroxide until the solid residue was dissolved, and the combined filtrates were acidified with 37% aqueous hydrochloric acid to pH 3. The precipitate was filtered off; an additional amount of the product precipitated overnight from the filtrate and was collected. The product was dried at 100° C. to give total 567 g (80%), m.p. 220° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:13][CH2:12][N:11]([C:20]2[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[C:22]([NH:28][C:29]3[N:34]=[C:33]([N:35](CC)[CH2:36][C:37]4C=CC(OC)=CC=4)[C:32]4=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:31]4[N:30]=3)[C:21]=2[Cl:52])[CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[Cl:52][C:21]1[C:22]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH3:37])[C:32]3=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:31]3[N:30]=2)=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:20]=1[N:11]1[CH2:12][CH2:13][C@@H:14]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@H:9]([OH:8])[CH2:10]1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O[Si](C)(C)C(C)(C)C)C3)c2Cl)nn2c(C#N)cnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 133.3 %

Procedure:
methyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (140 mg, 0.188 mmol) was dissolved into tetrahydrofuran (2 mL). TBAF 1M in THF (0.244 mL, 0.244 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness, then diluted with EtOAc (50 ml) and washed with sat. NaHCO3. The water layer was extracted with 20 ml EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to dryness to give 128 mg of product, which was used further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13]>C1COCC1>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)O)c2)cc1
Reaction time: 72 h

Procedure:
5-Amino-2-chloro-benzoic acid (0.355 g, 2.06 mmol) was diluted with THF (12 mL), treated with 4-cyano-benzoyl chloride (0.377 g, 2.23 mmol) and stirred for 72 h. Solvents were then removed and resulting solids were triturated with DCM. After filtration, the title compound was obtained as a white solid (0.6 g, 97%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([C:17]2[CH:26]=[CH:25][C:20]3[C:21](=[O:24])[O:22][CH2:23][C:19]=3[C:18]=2[CH3:27])[CH3:16])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:27][C:18]1[C:19]2[CH2:23][O:22][C:21](=[O:24])[C:20]=2[CH:25]=[CH:26][C:17]=1[CH:15]([CH3:16])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1c(C(C)CN2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1COC2=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O

Procedure:
tert-Butyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazine-1-carboxylate (160 mg, 0.43 mmol) was stirred in TFA (3 mL) at r.t for 3 hr. The reaction was concentrated and pump over high vacuum pump overnight to give the desired product, which could be converted to its freebase by partitioning between an organic solvent and saturated NaHCO3 solution. LC-MS (IE, m/z): 275.38 [M+1]+; tR=0.38 min.
Reaction SMILES: CSC.B(F)(F)F.[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([N:18]2[C:22]3[CH:23]=[C:24]([O:29]C)[C:25]([O:27]C)=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:15][C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:12])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[S:17][C:16]([N:18]2[C:22]3[CH:23]=[C:24]([OH:29])[C:25]([OH:27])=[CH:26][C:21]=3[N:20]=[CH:19]2)=[N:15][C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: CCOC(=O)c1sc(-n2cnc3cc(O)c(O)cc32)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 90.4 %

Procedure:
Boron trifluoride dimethylsulfide (4.1 ml, 39 mmol) was added in multiportions over 5 hrs. to a suspension of 2-(5,6-Dimethoxybenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (2.04 g, 4.99 mmol) in methylene chloride at RT. The mixture was stirred for an additional 40 mins. Ice water was added. Methylene chloride was removed, the residue was filtered, the solid was washed with water and a small amount of methanol, and then dried in air to give the product (1.72 g, yield 90%). 1H-NMR (DMSO-D6) 8.72 (s, 1H); 8.78-8.88 (m, 2H); 7.64 (s, 1H); 7.42-7.51 (m, 3H); 7.08 (s, 1H); 4.22 (q, 2H), 1.22 (t, 3H). MS M/z 382 (M+1)
Reaction SMILES: [C:1]([CH:4]1[CH:9]=[CH:8][CH2:7][N:6]2[C:10](=[O:18])[N:11]([CH2:14][C:15]([OH:17])=[O:16])[C:12](=[O:13])[N:5]12)([OH:3])=[O:2]>O1CCOCC1.[Pd]>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]2[C:10](=[O:18])[N:11]([CH2:14][C:15]([OH:17])=[O:16])[C:12](=[O:13])[N:5]12)([OH:3])=[O:2]
Reactant: O=C(O)Cn1c(=O)n2n(c1=O)C(C(=O)O)C=CC2
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)Cn1c(=O)n2n(c1=O)C(C(=O)O)CCC2
Yield: 66.1 %

Procedure:
0.75 g of 5-carboxy-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-acetic acid was dissolved in 50 ml of dioxan and hydrogenated in the presence of 10% palladium-on-charcoal at room temperature for 3 hours. The catalyst was filtered off and the filtrate was evaporated to give a colourless solid. This solid was recrystallized from acetonitrile to give 0.50 g (67%) of 5-carboxy2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-2-acetic acid of melting point 224°-226° C. (from acetonitrile).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1CCC(N=C=NC2CCCCC2)CC1.[C:36](O)(=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C1C=CN=CC=1)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([O:20][C:36](=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C(C)O)cc2)cc1
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCC(=O)OC(C)c1ccc(-c2ccc(CCCCC)cc2)cc1

Procedure:
Racemic (±)-4-pentyl-4'-(1-hydroxyethyl)biphenyl (m.p. 90.0° C.) was optically resolved by biochemical transesterification. Using the obtained 5.0 g of (-)-4- pentyl-4'-(1-hydroxyethyl)biphenyl (m.p. 83.8° C., [α]D 24.5 -25.0° (c 1.0, CH3OH)), 7.0 g of DCC, 1.0 g of DMAP and 3.0 g of caproic acid, optically active 4-pentyl-4'-(1-hexanoyloxyethyl)biphenyl 3.2 g was obtained by the same method as described in Example 1. The melting point of the obtained biphenyl was 10° C.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19].[CH:20]([O:22][CH2:23][CH3:24])=[CH2:21]>CCOCC>[CH2:20]([O:22][CH:23]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[CH3:24])[CH3:21]
Reactant: C=COCC
Reactant: OCCCCCCBr
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCOCC
Product: CCOC(C)OCCCCCCBr
Reaction time: 1 h

Procedure:
To a cooled solution of 80 mg of toluenesulfonic acid in 40 ml of ether was fed 20 g (110 mmol) of 6-bromohexanol and 40 ml of ethyl vinyl ether simultaneously by separate additional funnels. The temperature of the reaction mixture was kept at 7° C. or lower during the feeds, which took 1 hour. The reaction mixture was stirred 20 minutes longer, then roughly 1 ml of triethylamine was added. The reaction mixture was washed with water and brine, dried over potassium carbonate, filtered and stripped to give 25.7 g of a pale yellow liquid, which was used without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(Cl)ccc21
Yield: 74.4 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (200 mg), 167.6 mg 6-chloro-2-oxindole, and 166 μL piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven to give 246 mg (74%) of the title compound as a brown solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:28]=[CH:27][C:12]3[N:13]=[C:14]([N:16]4[CH2:20][CH2:19][C@@H:18]([N:21]5[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17]4)[S:15][C:11]=3[CH:10]=2)=[CH:5][N:4]=1.Br>>[N:21]1([C@@H:18]2[CH2:19][CH2:20][N:16]([C:14]3[S:15][C:11]4[CH:10]=[C:9]([C:6]5[CH:7]=[N:8][C:3]([OH:2])=[N:4][CH:5]=5)[CH:28]=[CH:27][C:12]=4[N:13]=3)[CH2:17]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1ncc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)cn1
Agent: Br
Product: Oc1ncc(-c2ccc3nc(N4CC[C@@H](N5CCCCC5)C4)sc3c2)cn1

Procedure:
A solution of (R)-6-(2-methoxypyrimidin-5-yl)-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 15, 20 mg, 0.051 mmol) in hydrobromic acid (48 wt. % in water, 0.25 mL, 2.2 mmol) was heated to 80° C. for 1 hour, concentrated with a stream of nitrogen and chromatographed on silica gel eluting with 2 to 20% (9:1 methanol:ammonium hydroxide) in CH2Cl2 to provide the desired product. 1H NMR (300 MHz, CD3OD) δ ppm 1.48-1.57 (m, 2H), 1.62-1.72 (m, 4H), 1.98-2.10 (m, 1H), 2.32-2.43 (m, 1H), 2.47-2.67 (m, 4H), 3.05-3.19 (m, 1H), 3.39-3.46 (m, 1H), 3.52-3.62 (m, 1H), 3.71-3.80 (m, 1H), 3.84-3.92 (m, 1H), 7.49 (dd, J=8.5, 1.7 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 8.59 (s, 2H); MS (DCI/NH3) m/z 382 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][C:10]1=[O:16]>C(O)C.O>[C:1]1([NH:7][NH:8][C:12]2[CH2:13][CH2:14][NH:9][C:10](=[O:16])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=C1CCNC(=O)C1
Solvent: CCO
Solvent: O
Product: O=C1C=C(NNc2ccccc2)CCN1

Procedure:
Phenylhydrazine (17.4 ml) was added over 15 min to a stirred suspension of 2,4-piperidinedione (20 g) in ethanol (200 ml) at ca. 20°. The resulting suspension was diluted with ethanol (80 ml) and water (300 ml) and the solid was filtered off to give the title compound (23.31 g), m.p. 165°-168°.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([N:18]=[C:19]=[O:20])(C)C.CO>C(#N)C>[S:1]([C:5]1[S:13][C:8]2[CH2:9][N:10]([C:19](=[O:20])[NH2:18])[CH2:11][CH2:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Solvent: CC#N
Product: NC(=O)N1CCc2cc(S(N)(=O)=O)sc2C1
Reaction time: 19 h
Yield: 95 %

Procedure:
To a warm (40° C.) solution of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.42 g, 6.5 mmol) in acetonitrile (80 ml), under a nitrogen atmosphere, was added trimethylsilyl isocyanate (1.0 ml, 7.4 mmol). This solution was stirred for 19 hours and then methanol (2 ml) was added. After 2 hours the precipitated pure product was collected by filtration (1.62 g, 95% yield); m.p. 205°-208° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][C:2]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1COCC1.O=[Mn]=O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][C:2]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: OCc1ccnc(-c2ccccn2)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1ccnc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A solution of [2,2′-bipyridin]-4-ylmethanol (120 mg; 0.64 mmol) in anh. THF (5 ml) was treated with MnO2 (873 mg; 10.05 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 6.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with THF. The filtrate was concentrated to dryness under reduced pressure giving [2,2′-bipyridine]-4-carbaldehyde as a colorless solid. LC-MS (conditions A): tR=0.30 min.; [M+H]+: 185.17 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=[C:14]([C:25]([O:27]C)=[O:26])[CH:13]=1.O1CCCC1.[OH-].[Li+]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:11])[F:10])[C:3]=1[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=[C:14]([C:25]([OH:27])=[O:26])[CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2c(F)cccc2C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3c(F)cccc3C(F)(F)F)c2)nc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A round bottom flask was charged with methyl 2′-fluoro-5-(5-methylpyridin-2-yl)-6′-(trifluoromethyl)biphenyl-3-carboxylate (200.00 mg, 0.51368 mmol), Tetrahydrofuran (7.8 mL, 97 mmol) and Lithium hydroxide (36.906 mg, 1.5410 mmol) and the reaction stirred at room temperature over night and at 50° C. for two days. The reaction mixture was filtered over Sodium sulfate and the solvent removed under reduced pressure to get the acid as brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:16]([O:18][C:19]([CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])[CH:12]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: CN(C)C(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(C(=O)N(C)C)c2)CC1

Procedure:
5-Chloro-N,N-dimethyl-2-nitrobenzamide (1.131 g), 4-piperidinecarboxylic acid ethyl ester (0.77 mL), and potassium carbonate (1.4 g) were reacted in N,N′-dimethylformamide (20 mL) at 100° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated to give the title compound (1.578 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:17]([CH2:25][CH2:26][N:27]=4)[C:18]([NH2:24])=[N:19][C:20]=3[C:21]=2[O:22][CH3:23])[CH2:4][CH2:3]1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>>[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:24][C:18]2[N:17]3[CH2:25][CH2:26][N:27]=[C:16]3[C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:28])[CH2:3][CH2:4]4)=[C:21]([O:22][CH3:23])[C:20]=3[N:19]=2)=[O:35])=[CH:32][N:31]=1
Reactant: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ccc(C(=O)O)cn1
Product: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-[3-(1,1-dioxidothiomorpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (135 mg, 69%): HPLC MS RT=1.16 min, MH+=528.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.24-2.29 (2H, m), 3.43-3.49 (2H, m), 3.60-3.62 (4H, m), 3.82 (4H, bs), 3.99 (3H, s), 4.23-4.27 (2H, m), 4.33 (2H, t), 4.48-4.54 (2H, m), 7.05 (1H, d), 7.44 (1H, d), 8.04 (1H, d), 8.47 (1H, dd), 8.77 (1H, d).
Reaction SMILES: [NH:1]([C:49](OC(C)(C)C)=[O:50])[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[N:56]1([C:77]2[CH:88]=[CH:87][C:83]([N+:84]([O-:86])=[O:85])=[CH:82][C:78]=2[N+:79]([O-:81])=[O:80])[CH2:76][CH2:75][CH2:74][C@H:57]1C(N[C@H](C(NCC(O)=O)=O)CCC(=O)N)=O>>[N:56]1([C:77]2[CH:88]=[CH:87][C:83]([N+:84]([O-:86])=[O:85])=[CH:82][C:78]=2[N+:79]([O-:81])=[O:80])[CH2:76][CH2:75][CH2:74][C@H:57]1[C:16]([NH:18][C@H:19]([C:25]([NH:27][CH2:28][C:49]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:50])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17]
Reactant: NC(=O)CC[C@H](NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)NCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Leu-Ala-Gly-Gln-D-Arg(NO2)-OBzl (350 mg, 0.45 m mol) was demasked with respect to the N-masking group and coupled with DNP-Pro-Gln-Gly-OH (210 mg, 0.45 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: [O:1]=O.[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6]>>[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:1])([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6]
Reactant: COC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=O
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Yield: 42 %

Procedure:
The oxidization in an oxygen atmosphere was conducted in the same manner as in Preparation Example 1 except that 1-methoxycarbonyladamantane was used instead of the adamantane, and, as a result, a 1-methoxycarbonyl-3-hydroxyadamantane (yield: 42%) and a 1-methoxycarbonyl-3,5-hydroxyadamantane (yield : 33%) were obtained with a conversion of 91%.