Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:23])[CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:23][CH:7]([CH2:6][O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:8][C:9]1([OH:22])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OCC(O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
2.59 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate was dissolved in 10 ml dimethylformamide, 400 mg of sodium hydride and 823 mg of benzyl chloride were added thereto, and the mixture was stirred at room temperature for 20 min. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was-purified by silica gel column chromatography (hexane/ethyl acetate) to give 2.66 g of tert-butyl 4-(2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](Br)(Br)([Br:15])[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[C:4]([CH:5]=[C:13]([Br:15])[Br:14])[C:3]=1[CH2:11][CH3:12]
Reactant: CCc1c(Cl)ccc(F)c1C=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCc1c(Cl)ccc(F)c1C=C(Br)Br

Procedure:
1-Chloro-3-(2,2-dibromo-vinyl)-2-ethyl-4-fluoro-benzene was prepared from 3-chloro-2-ethyl-6-fluoro-benzaldehyde, carbon tetrabromide and triphenylphosphine in analogy to Example 1d): colourless oil; 1H-NMR (CDCl3): 1.15 (3H, t, CH3), 2.72 (2H, q, CH2), 6.90 (1H, dd, ArH), 7.29 (1H, s, CH═CBr2), 7.33 (1H, dd, ArH).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>CN(C=O)C.CCOC(C)=O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CCNCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 115 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (1.44 g, 3.33 mmol, Intermediate 3: step c) and diethylamine (6.91 mL, 66.5 mmol) in DMF (10 mL) in a sealed tube was heated in a 115° C. oil bath for 23 h. The mixture was diluted with EtOAc and extracted with water (5×, sat. aq. NaCl added as needed to achieve phase separation). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, dry loading, 2-10% EtOAc-heptanes first column, 0-4% EtOAc-heptanes second column) to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](I)=[CH:10][N:11]=2)[N:5]=[C:6](Cl)[CH:7]=1.[BrH:13].O>C(O)(=O)C>[Br:13][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Br
Reactant: Clc1cc(Br)c2ncc(I)n2n1
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc(Br)c2nccn2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 5.0 (14.0 mmol) 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine which was prepared according to intermediate example 1c, 30 mL of hydrogen bromide solution in acetic acid (33%) was stirred at 120° C. for 1 hour under microwave irradiation. The mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sodium thiosulfate and sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 3.0 g (78%) of the title compound.
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH2:32][C:29]2([O:31][CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:33][CH2:32][C:29]([CH2:30][F:1])([OH:31])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CF)CC1
Yield: 19.9 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 5.6 ml, 5.6 mmol) was added to a solution of 1-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (400 mg, 1.87 mmol) in tetrahydrofuran (5 ml), and the mixture was heated under reflux for 36 hours. The reaction solution was cooled and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 4-fluoromethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (87 mg, 19%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=O)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCNC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (12.25 mmol) in dichloromethane (84 mL) was added a solution of hydrogen chloride in 1,4-dioxane (28 mL, 4M). The reaction mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to afford (R)-piperidine-3-carboxylic acid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=C[N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52](C#N)=[CH:51][CH:50]=2)N=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:52]3[CH:55]=[CH:56][C:49]([C:48]#[N:45])=[CH:50][CH:51]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: N#Cc1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C#N)cc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 4-(3-amino-pyrazol-1-ylmethyl)-benzonitrile (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(4-cyano-benzyl)-1H-pyrazol-3-yl]-3-cyclopentyl-propionamide (35 mg, 23%) as a white solid: ESI-LRMS m/e calcd for C26H27ClN4O3S [M+] 510.2, found 511.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.21 (m, 2H, CH2), 1.44-1.92 (m, 8H, 4×CH2), 2.09-2.35 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.56 (t, J=7.5 Hz, 1H, CH), 5.20 (s, 2H, NCH2), 6.74 (d, J=2.3 Hz, 1H, Ar), 7.19 (d, Jo=8.4 Hz, 2H, Ar), 7.35 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.54-7.63 (m, 3H, Ar), 7.99 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CN1CCCC1=O.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>O>[C:22]([NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a mixture of 5.22 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.88 g of tert-butylamine, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure, to obtain 5.35 g of N-tert-butyl-2-nitro-4-trifluoromethylaniline.
Reaction SMILES: [CH:1]1([C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)(O)[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:6][CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1
Reactant: C=CC(O)(c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: FC(F)(F)Oc1ccc(C(=CCCl)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Under a nitrogen atmosphere a solution of 130.0 grams (0.5 mole) of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-2-propen-1-ol and 49.3 grams (0.54 mole) of pyridine in 500 mL of methylene chloride was stirred, and 60.2 grams of thionyl chloride was added dropwise during a 30 minute period. The reaction mixture was maintained at 0° to 10° C. throughout the addition. Upon completion of addition the reaction mixture was stirred for 1 hour and then was diluted with 500 mL of methylene chloride and 500 mL of ice. The mixture was stirred until the ice melted. The organic layer was separated and was in turn washed with two 500 mL portions of aqueous 0.5N hydrochloric acid, two 500 mL portions of an aqueous solution saturated with sodium bicarbonate, two 500 mL portions of water, and two 500 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 113.5 grams of 3-chloro-1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-1-propene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=2)=[CH:4][C:5]([C@@:9]2([CH2:48][C:49]([CH3:51])=[CH2:50])[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[C:6]([OH:8])[CH:7]=1.CCOC(C)=O>ClC(Cl)C.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:10][C@:9]21[C:5]1[C:6](=[CH:7][C:2]([Cl:1])=[C:3]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([CH2:59][CH3:60])=[CH:55][CH:54]=3)[CH:4]=1)[O:8][C:49]([CH3:51])([CH3:50])[CH2:48]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C(C)C[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(C)(C)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 70 °C
Yield: 39.8 %

Procedure:
A mixture of 25 (48 mg, 58 μmol) and silver triflate (15 mg, 58 μmol) in dichloroethane (1 mL) was heated to 70° C. for 2 h. LC/MS indicated that the conversion was complete to give a new and less polar component. After cooling, the mixture was loaded onto a TLC plate and developed using 10% EtOAc in petroleum ether to give 56 (19 mg, 40%). LC/MS m/z 846 (M+Na), 824 (M+1).
Reaction SMILES: [CH2:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH2:4][CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CCCCCC>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: C1=CCC2=C(C1)CCc1ccccc1C2
Reactant: ClCCN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 0.5 h

Procedure:
1.0 g of 1,4,10,11-tetrahydro-5H-dibenzo[a,d]cycloheptene in 20 ml of dry tetrahydrofuran are treated dropwise at between -70° and -60° with 9.0 ml of an about 0.85M solution of n-butyl lithium in hexane. The mixture is stirred at -70° for 60 minutes and at -30° for 30 minutes, a solution of 2.1 g of 2-chloroethylpyrrolidine in 5 ml of dry tetrahydrofuran at -30° is added dropwise thereto and subsequently the mixture is stirred at -30° for an additional 30 minutes, at 0° to 5° for 3 hours and at room temperature for 30 minutes. After evaporation of the mixture, the residue remaining is dissolved in toluene and washed ion-free with water. The organic phase is filtered over aluminum oxide (activity grade II, neutral) using toluene for the elution. Crude 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine is obtained.
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)[NH:42][CH2:43][CH2:44][C:45]2C=[CH:49][C:48](OC3C=CC=CC=3)=[CH:47][CH:46]=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCCCCCCNC(=O)C(C)(C)Oc1ccc(C[C@H](OCC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and hepthylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H33NO5 [M+H]+: 394.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH:9]1([CH2:12][NH:7][C:2]2[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: O=CC1CC1
Reactant: Nc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccccc1NCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzene-1,2-diamine (1.62 g, 15.0 mmol) and cyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in MeOH (15 mL) at 0° C. was added NaCNBH3 (2.07 g, 33.0 mmol) and acetic acid (0.2 mL). The ice bath was removed and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-cyclopropylmethyl-benzene-1,2-diamine MS 163 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=O.Cl.[NH2:22][OH:23].CO>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:6]([CH3:18])=[C:5]2[CH:19]=[N:22][OH:23]
Reactant: Cc1c(C=O)c2cc(Br)ccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1c(C=NO)c2cc(Br)ccc2n1-c1ccc(O)cc1
Yield: 66 %

Procedure:
A mixture of 5-bromo-1-(4-hydroxyphenyl)-2-methyl-1H-indole-3-carbaldehyde (0.16 g, 0.5 mmol), hydroxylamine hydrochloride (0.10 g, 1.4 mmol), methanol (10 mL) and pyridine (0.2 mL) was reacted according to the procedure used in Example 4 to afford a white solid (66%): mp 209-211° C.; 1H NMR (DMSO-d6): δ 2.29 (3H, s), 6.92-6.97 (3H, m), 7.20-7.25 (3H, m), 8.19 (1 H, d, J=1.9 Hz), 8.39 (1H, s), 9.94 (1H, br s), 10.76 (1H, s); MS m/z (M+H)+ 345/347 (1 Br). Anal. for C16H13BrN2O2·0.5H2O; Calc'd: C, 54.26; H, 3.98 N, 7.91. Found: C, 54.26; H, 3.68; N, 7.65.
Reaction SMILES: C([O-])(=O)C.[K+].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[CH:15][C:8]=12.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.O>CCO>[F:16][C:17]1[C:22]([C:7]2[N:12]=[CH:11][N:10]=[C:9]3[NH:13][N:14]=[CH:15][C:8]=23)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Fc1ncccc1-c1ncnc2[nH]ncc12
Temperature: 25 °C
Yield: 40 %

Procedure:
A degassed mixture of potassium acetate (1.9 g, 19 mmol), PdCl2(PtBu2Ph)2 (0.16 g, 0.26 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.00 g, 6.5 mmol) and 2-fluoropyridin-3-ylboronic acid (1.1 g, 7.8 mmol) in EtOH (30 mL)-water (10 mL) was sonicated until the solid became a fine powder. The mixture was refluxed under N2 overnight. After cooling to rt, solvent was removed in vacuo and water (50 mL) and NaHCO3 (sat. 100 mL) were added to the residue. The mixture was extracted with EtOAc (3×100 mL). The solid was filtered and washed with water. The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered through celite and concentrated in vacuo to give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (0.56 g). The previous solid was dissolved in MeOH-DCM and preloaded on silica gel and purified by flash column chromatography eluting with MeOH/DCM (1-5%) to give give 4-(2-fluoropyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.4 g). The two product crops were combined (65% overall). MS (ESI, pos. ion) m/z: 216 [M+H]+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:33]1[CH2:35][C@@H:34]1[CH2:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][N:16]([CH2:35][C@@H:34]([OH:33])[CH2:36][O:37][C:38]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:39]=3[CH:40]=[CH:41][CH:42]=[N:43]4)[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCc1ccccc1)[C@H]1CCNC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NCCCCc1ccccc1)[C@H]1CCN(C[C@@H](O)COc2cccc3ncccc23)C[C@H]1C(=O)NCCCCc1ccccc1
Temperature: 70 °C
Yield: 82.8 %

Procedure:
cis-Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide] (9) (70.9 mg; 0.163 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (32.8 mg; 0.163 mmol) is added then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→50% methanol in methylene chloride) affording the desired product (86.0 mg) as an oil. ESMS: MH+ 637.4 (base).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1.C(Cl)[Cl:32]>S(Cl)(Cl)=O>[Cl:32][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([N:26]5[CH:30]=[CH:29][CH:28]=[CH:27]5)[CH:24]=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[O:6][CH:7]=1
Reactant: ClCCl
Reactant: O=C1CC(c2cccc(-c3nc(CO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2cccc(-c3nc(CCl)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-[3-(4-hydroxymethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 26) (1.0 g) in CH2Cl2 (15 mL) and thionyl chloride (0.27 mL) was heated with stirring to 40° C. for 0.5 h and subsequently cooled in the ice bath. The solid was isolated by filtration and washed with CH2Cl2 to give 4-[3-(4-chloromethyl-oxazol-2-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (1.0 g) as yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:6]([O:5][CH:2]([CH:3]1[CH2:4][O:30]1)[CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C)OCCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(C)C1CO1
Reaction time: 8 h

Procedure:
A mixture of 46.9 g of 1-[(1-methyl-2-propenyl)oxy]hexadecane, 32.19 g of m-chloroperbenzoic acid and 300 ml of methylene chloride was stirred overnight and then filtered. The filtrate was evaporated and the residue dissolved in petroleum ether:ether and washed with saturated aqueous sodium bicarbonate. The solution was dried, the solvent removed and the residue chromatographed via HPLC (two columns), eluting first with hexane to remove higher Rf impurities and then with 10% ether in hexane to elute the product, giving the desired compound as a clear oil.
Reaction SMILES: [NH3:1].[CH3:2][C:3]([O:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:15](OC1C=CC([N+]([O-])=O)=CC=1)=[O:16])=[O:8])([CH3:5])[CH3:4]>C1COCC1>[CH2:31]([O:30][C:28]([NH:27][C@H:14]([C:15]([NH2:1])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O

Procedure:
A stream of NH3 was passed over a solution of Z-Lys(Boc)ONp (10.2 g, 2.0 mmole, Bachem) in THF (200 ml) for about 3 hr. A precipitate formed. The solvent was removed and the residue triturated and thoroughly washed with ether. The dried protected amide weighed 5.8 g (75%), m.p. 140°-142°, [α]D24 +1.9° (c 1.3. DMF): RfB, 0.54; RfG, 0.54.