Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nc(CN3CCCC3)no2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.4 g (0.006 mole) of pyrrolidine in DMF (10 ml) is stirred at room temperature for three hours. The mixture is poured into ice water (50 ml) and extracted with ethyl acetate (3×25 ml). The organic phase is washed with water (3×40 ml), dried (anhydrous magnesium sulfate), and evaporated, leaving an oil. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) yields 0.4 g (73%) of analytically pure 2,6-bis(1,1-dimethylethyl)-4-[3-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol-5-yl]phenol, mp 100°-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][CH2:10]CCC.Br[C:15]1C=NC=CC=1C=O.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[C:9]([CH3:10])[CH3:15]
Reactant: O=Cc1ccncc1Br
Reactant: CCCCC=Cc1ccncc1Br
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Product: CC(C)=Cc1ccncc1Br

Procedure:
Following the general method as outlined in Intermediate 12, starting from 3-bromo-4-pyridinecarboxaldehyde (Aldrich) and isopropyltriphenylphosphonium iodide, the title compound was obtained as a yellow liquid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[N:14]([CH2:20][CH3:21])[C:15](=[O:19])[C:16](=O)[NH:17][C:12]=2[CH:11]=[N:10]1.O=P(Cl)(Cl)[Cl:24].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:24][C:16]1[C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]2[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=[CH:11][C:12]=2[N:17]=1
Reactant: CCn1c(=O)c(=O)[nH]c2cnn(-c3ccc(F)cc3F)c21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(=O)c(Cl)nc2cnn(-c3ccc(F)cc3F)c21
Temperature: 110 °C

Procedure:
A mixture of 1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione (330 mg, 1.13 mmol) in 5 mL of toluene was treated with POCl3 (0.16 mL, 1.70 mmol) followed by N,N-diisopropylethylamine (0.16 mL, 0.9 mmol). The reaction mixture was heated in an oil bath at 110° C. for 2.5 h. The volatiles were removed on the rotovap and the residue was dissolved in ice cold DCM (20 mL) and washed with NaHCO3 saturated solution, dried over MgSO4, filtered and concentrated affording 5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one as a brown amorphous solid. The material was used without further purification. MS (ES+): 311.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:17]([CH2:18][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][CH3:21])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Cl)=[O:7])=[CH:4][C:3]=1[Br:28].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45]([O-:47])=[O:46].[Na+].Cl>>[NH2:1][C:2]1[C:17]([CH2:18][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:20][CH3:21])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:47][C:45](=[O:46])[CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[NH:37][C:31]2[C:30]([Cl:29])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:36])=[O:7])=[CH:4][C:3]=1[Br:28]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CCN(Cc1cc(C(=O)NCCCCCCCl)cc(Br)c1N)C1CCCCC1
Agent: Cl
Agent: [Na+]
Product: CCN(Cc1cc(C(=O)NCCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 6-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzamido]-n-hexyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8. Amorphous hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[N:4]=[CH:3]1.[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1.ClCCl>C(#N)C>[O:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH2:13][CH2:12]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NCCCN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NCCCN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of 30 g (0.17 mol) of 1-methylimidazole-4-sulfonyl chloride from Example C-1 in 150 ml of acetonitrile is added dropwise to a solution of 24 ml (0.17 mol) of 3-morpholinopropylamine in 50 ml of acetonitrile (or dichloromethane). The temperature of the reaction mixture is kept at room temperature or below by external cooling with ice-water. Stirring is continued for 6 h at room temperature. The precipitate deposited is filtered off with suction and recrystallized from acetonitrile in order to give 46 g (85% of theory) of the title compound (hydrochloride) of melting point 207°-208° C.
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[O:7])[CH:2]=1.[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)n2ccnc2)C1
Temperature: 57.5 °C
Yield: 88.1 %

Procedure:
To a suspension of CDI (3.8 g, 20.5 mmol) in THF (40 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester (3.99 g, 20.5 mmol) and the reaction mixture was heated at about 55-60° C. for about 4 h. The reaction mixture was cooled at ambient temperature and concentrated in vacuo to afford an yellow oil. The residue was dissolved in DCM (40 mL), washed with water (2×30 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give [1-(imidazole-1-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (5.06 g, 88%) as a yellow oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.08 min; m/z: (M+H)+ 281.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]([C:15]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([OH:14])=[O:13]>O.CC(C)=O>[CH2:11]([N:18]1[CH2:19][CH2:20][C:15]([C:12]([OH:14])=[O:13])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
106 ml of a 30% NAOH solution is added to a suspension of 100 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 600 ml of water, then the thus obtained solution is cooled to 5° C., a solution of 47.6 g of bromide benzyl in 100 ml of acetone is added dropwise and left under stirring for 1 hour while the temperature being allowed to rise to RT. The acetone is evaporated under vacuum, and the pH of the remaining aqueous phase is brought to 9.5 by adding concentrated aqueous solution of HCl, then the pH is adjusted to 8.5 by adding a 2N HCl solution. The precipitate formed is wrung and washed with water and then with acetone to give 70 g of the expected compound, M.p.=286° C.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=2)[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH2:30])=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(Cl)Cl>[I:18][CH:29]1[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:42]=2)[C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH2:30]1
Reactant: C=CC(c1ccccc1)C(c1ccc(OC)cc1)c1ccc(OC(=O)C(C)(C)C)cc1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (65.8 mg, 0.177 mmol) was suspended in methylene chloride (3.4 mL), and cooled in a dry ice-acetone bath to −78° C. To this, a methylene chloride (1.8 mL) solution of 1-(4-methoxyphenyl)-2-phenyl-1-(4-pivaloyloxyphenyl)-3-butene (4, 56.0 mg, 0.135 mmol) was added, and further, boron tribromide diethyl ether complex (0.015 mL, 0.118 mmol) was added divided into 3 portions. After this, and after stirring for 1 hr at −78° C., the reaction was stopped by adding a saturated ammonium chloride solution (5 mL), and after returning to room temperature, extraction was performed three times with diethyl ether (10 mL). The organic layers were combined and washed with a saturated sodium chloride solution (10 mL), dried with anhydrous sodium sulfate, and concentrated. The residue was purified with thin layer chromatography (toluene), and the subject compound (5, 51.6 mg) was obtained as a slightly yellow oily substance (yield 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].[F:37][CH:38](O)[CH3:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:39][CH2:38][F:37])[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25]
Reactant: CC(O)F
Reactant: COc1ccc(Cn2c(=O)c3cc(O)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cc(OCCF)ccc3n(C3CCOCC3)c2=O)cc1OC
Yield: 95.4 %

Procedure:
A mixture of 0.2 g of 3-(3,4-dimethoxybenzyl)-6-hydroxy-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione and 0.32 g of Cs2CO3 in 10 ml of DMF is irradiated in a microwave field for 1 minute at 100° C. 0.169 g of fluoroethanol are then added and the mixture is irradiated in a microwave field for 5 minutes at 140° C. The reaction medium is evaporated under reduced pressure. The residue is taken up in EtOAc and washed with water and then with saturated NaCl solution. The resulting solution is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to give 0.212 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][C@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][C@@H:23]([NH:22][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:29]=[CH:28][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])[C:24]([N:34]1[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]1)=[O:25]
Reactant: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)O
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C)C(=O)N1CCN(C)CC1
Yield: 33.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (20 mg) was prepared by following General Procedure F starting from (R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid (50 mg), 1-methyl-piperazine (50 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 511.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.82-8.67 (m, 1H), 8.12 (m, 1H), 7.97 (s, 1H), 7.85-7.83 (m, 1H), 7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 5.02-4.96 (m, 1H), 4.50-4.43 (m, 1H), 4.35-4.19 (m, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 2H), 3.45 (m, 1H), 3.28 (m, 1H), 3.10 (m, 1H), 2.78-2.77 (d, 3H), 1.44-1.35 (m, 3H)—NH proton signal was not observed.
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[N:57]=[CH:56][CH:55]=[N:54]1)=[O:45].Cl[C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[N:60]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44]([C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[N:57]=[CH:56][CH:55]=[N:54]2)=[O:45])[C@@H:37]1[CH2:36][NH:35][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[N:60]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2cccc(C(F)(F)F)n2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-6-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CCN(CC)CC>C1(C)C=CC=CC=1>[CH:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCO
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCC=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of N-chlorosuccinimide (0.1 g, 0.8 mmol) in toluene (2 mL) was added flurous sulfide 1 (0.4 g, 1 mmol) at 0° C. resulting in the immediate formation of a white cloudy precipitate. The reaction mixture was cooled to −25° C., and a solution of octanol (0.07 g, 0.5 mmol) in toluene (2 mL) was added. After stirring at −25° C. for 2 hours, a solution of Et3N (0.08 g, 0.8 mmol) was added. The cold bath was removed after 5 minutes, and the reaction mixture washed with saturated aqueous NH4Cl, then water. The organic layer was extracted continuously with FC72 solvent (15 mL) in a cooled continuous extractor for a period of 4 hours. Concentration of the toluene layer and chromatography on silica gel (eluent: EtOAc/hexanes 3:1) yielded octanal (0.06 g, 88%). The FC72 layer was carefully concentrated under aspirator vacuum to give recovered fluorous sulfide 1 (0.3 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A mixture of 3-(4-fluorophenyl)propionic acid (275.1 g, 1.6 mol) and thionyl chloride (300 mL, 4.1 mol) was heated to reflux for 3 h, cooled to room temperature and distilled under aspirator vacuum to give 287.6 g (96%) of 3-(4-fluorophenyl)propionyl chloride as a pale pink oil, b.p., 120°-122° C./15 mm Hg:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([C:23]([OH:25])=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([C:23]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][N:14]=3)=[O:25])[CH2:39][CH2:40]2)=[CH:29][CH:28]=1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: Fc1ccc(CCN2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1nccc2ccccc12)N1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.9 g of 1,1′-carbonyldiimidazole is added to a solution of 1 g of isoquinoline-1-carboxylic acid in 100 ml of tetrahydrofuran (THF), and the mixture is stirred at room temperature for 2 hours. 1.6 g of 1-[2-(4-fluorophenyl)ethyl]piperazine and 2.4 ml of triethylamine are added to this mixture, which is stirred for a further 80 hours. ConventionaL work-up gives {4-[2-(4-fluorophenyl)ethyl]piperazin-1-yl}isoquinolin-1-ylmethanone.
Reaction SMILES: N#N.[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH:16]=[O:17])=[CH:14][N:15]=1)[CH3:10])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+].O>CO>[C:3]([Si:7]([CH3:19])([CH3:18])[O:8][CH:9]([C:11]1[O:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=1)[CH3:10])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ncc(C=O)o1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc(CO)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-oxazole-5-carbaldehyde (457 mg, 1.79 mmol) was dissolved in MeOH (8 mL). NaBH4 (92 mg, 2.33 mmol) was added portionwise at 0° C. and the reaction mixture stirred at rt for 20 min. Water (16 mL) was added and the MeOH removed under reduced pressure. The mixture was then extracted with EA (2×20 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The title compound was obtained as a colorless oil. LC-MS-conditions 02: tR=0.97 min; [M+H]+=258.37.
Reaction SMILES: [NH3:1].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([O:13]C)=O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C:11]([NH2:1])=[O:13]
Reactant: N
Reactant: COC(=O)C1Cc2ccccc2N1
Solvent: CO
Product: NC(=O)C1Cc2ccccc2N1
Reaction time: 18 h
Yield: 85 %

Procedure:
Gaseous NH3 was bubbled into a solution of methyl (±)-indoline-2-carboxylate (4.3 g, 24.2 mmol) in methanol (50 mL) at RT for 30 min. The reaction was stirred for 18 h, then was filtered to afford the title compound (3.35 g 85%) as a colorless solid: MS (ES) m/e 163.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:12].[Na+:13].Cl>O1CCOCC1.O>[Na+:13].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)([O-])c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-3-pyridinesulfonyl chloride (5.0 g, 24 mmol) (C. Rath. Annalen. 1931, 487, 105-119) in dioxane (10 ml) and the solution cooled to 0° C. A solution of sodium hydroxide (1.88 g, 47 mmol) in water (20 ml) was added drop-wise to the stirred solution over 10 mins. After another 10 mins 0.5 pellet of NaOH was added and after a further 15 minutes the pH was adjusted to pH 7 with 2M hydrochloric acid and the solvent was vacuumed down. The material was dried on a Dean and Stark trap to give the title compound. MS (ES−) 192/194 [M−H]−.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)[CH:33]=[CH:34][C:35](O)=[O:36])([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH:34]=[CH:33][C:32]1[CH:38]=[CH:39][CH:40]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1cccc([N+](=O)[O-])c1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 52 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3-nitrocinnamic acid under the conditions described in example 86 to yield 52% of the desired product.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][C:8]=1[O:23][CH2:24][CH2:25][CH3:26])\[CH3:6])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1]/[C:2](=[C:5](/[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH3:22])([CH3:21])[CH2:12][CH:13]=[C:14]2[C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:9][C:8]=1[O:23][CH2:24][CH2:25][CH3:26])\[CH3:6])/[CH:3]=[O:4]
Reactant: CCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)(C)C)=CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)(C)C)=CCC2(C)C

Procedure:
As described in General Procedure H-1, (2E)-2-fluoro-3-(4,4 - dimethyl-6-n-propoxy-1-tert-butyl-3,4-dihydronaphthalen-7-yl)-2-butenol (Compound A-57, 0.027 g, 0.075 mmol), tetrapropylammonium perruthenate (12 mg, 0.038 mmol) and 4-methylmorpholine N-oxide (22 mg, 0.19 mmol) were reacted in acetonitrile (0.2 mL) and dichloromethane (1 mL) to produce the title compound as an oil.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:41][N:40]=[N:39][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[CH:38]=3)[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1([C:5]2[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH3:15])[N:6]=2)[CH2:4][CH2:3]1.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:16][C:9]1[C:5]([C:2]2([Cl:1])[CH2:4][CH2:3]2)=[N:6][N:7]([CH3:15])[C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cl)c(C2(Cl)CC2)nn1C
Temperature: 80 °C

Procedure:
500 mg (2.19 mmol) of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate are dissolved in 10 ml of N,N-dimethylformamide p.a., and 438 mg (3.28 mmol)) of N-chlorosuccinimide are added. The reaction mixture is heated at 80° C. for 15. The cooled reaction solution is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is filtered through silica gel and eluted with ethyl acetate. This gives 517 mg (80%) of ethyl 4-chloro-3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate in a purity of 89%.