Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N=C1CCCS1.C1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.FC(F)(F)C(O)=O.O=C1C=CC(=O)N1CCC(NC[CH:53]1[O:57][C:56]2[CH:58]=[CH:59][C:60]([CH2:62][CH:63]([NH:65][CH2:66][CH3:67])[CH3:64])=[CH:61][C:55]=2[O:54]1)=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CN(C=O)C>[CH3:67][CH2:66][NH:65][CH:63]([CH2:62][C:60]1[CH:59]=[CH:58][C:56]2[O:57][CH2:53][O:54][C:55]=2[CH:61]=1)[CH3:64]
Reactant: CCNC(C)Cc1ccc2c(c1)OC(CNC(=O)CCN1C(=O)C=CC1=O)O2
Agent: N=C1CCCS1
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Keyhole limpet hemocyanin (KLH, 60 mg) was reconstituted in 100 mM sodium phosphate buffer at pH 7.2. 2-Iminothiolane (2IT, 13.5 mg) was added to the protein solution as a solid, and the reaction was allowed to stir at room temperature in the dark and under argon atmosphere for 1 hour. The activated KLH—(SH)n was desalted on a Sephadex PD-10 column pre-equilibrated with 100 mM sodium phosphate buffer at pH 6.5. The SH loading was determined (Ellman's reagent) to be 886 per KLH molecule (MW 5,000,000). To 6 ml of KLH—(SH)n, 4.7 mg/mL, was added a solution of 14 mg (0.027 mmol) of MDEA-maleimide (2O) in 1 mL of DMF dropwise, and the mixture was allowed to stir at room temperature 18 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of phosphate buffered saline (PBS) buffer (180 mM NaCl, 10 mM sodium phosphate, pH 7.2] containing 20% DMF. (3 times, at least 6 hours each). This was followed by 1 L of PBS buffer, pH 7.2 at 4° C. The protein concentration was determined to be 2.08 mg/mL using Biorad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 20 mL of the conjugate was obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[Cl:68])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[N:59]1[C:55]2=[N:56][CH:57]=[N:58][C:53]([O:52][C@@H:41]([CH2:40][O:39][CH2:38][CH2:37][OH:36])[C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:43])=[C:54]2[CH:61]=[N:60]1
Reactant: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COCCO)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.271 mL, 0.27 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyridin-2-yl)propanamide (Intermediate AG4) (96 mg, 0.14 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (10 mL), extracted with Et2O (3×15 mL), the combined organic layers were back washed with water (10 mL), dried (MgSO4), and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in DCM to afford the product (50.0 mg, 79%). 1H NMR (400 MHz, CDCl3) δ2.28 (s, 3H), 3.32 (s, 1H), 3.70-3.81 (m, 4H), 4.13-4.26 (m, 2H), 6.08 (t, 1H), 7.43-7.55 (m, 4H), 7.59-7.63 (m, 1H), 8.05-8.10 (m, 2H), 8.44 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H); m/z (ESI+) (M+H)+=469.45; HPLC tR=1.86 min
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[O:24]([C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)[N+:25]([O-:27])=[O:26]>O1CCCC1>[O:24]([C@H:28]1[CH2:29][CH2:30][C@H:31]([NH:34][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)[CH2:32][CH2:33]1)[N+:25]([O-:27])=[O:26]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)N[C@H]2CC[C@H](O[N+](=O)[O-])CC2)N1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
2.1 g (0.016 mol) (S)-pyroglutamic acid (2-pyrrolidinone-5-carboxylic acid) are dissolved in 50 ml abs. tetrahydrofuran and 2.5 ml (0.018 mol) triethylamine. With cooling to about 5° C., 2 ml (0.016 mol) pivaloyl chloride in 10 ml abs. tetrahydrofuran are added dropwise thereto. After 15 min stirring at 5° C., one adds dropwise thereto a solution of 3.9 g trans-4-nitroxycyclohexylamine in 40 ml abs. tetrahydrofuran and 2.8 ml (0.02 mol) triethylamine. Thereafter, one allows to stir for 2 d at room temperature, filters off with suction and removes the solvent in a vacuum. The residue is dissolved in ethyl acetate and shaken out with sodium hydrogen carbonate. After drying of the ethyl acetate phase with sodium sulphate, distilling off in a vacuum, trituration with ether and suction filtration, there remain 1.5 g of the title compound of the melting point 166° C., i.e. 35% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH2:13][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc(O)cc1
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 88 %

Procedure:
The title compound was prepared from methyl 4-hydroxybenzoate and 2-chloromethylquinoline using methods as described in the literature for similar compounds (Musser et al., 1990) in 88% yield.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:21]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C
Yield: 140.1 %

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, butane 1-iodide 0.70 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 10 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.84 g.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([O-])([O-:21])=[O:20].[Na+]>FC(F)(F)C(O)=O.C(Cl)Cl>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-:21])=[O:20]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
(+,−) Cis-propane-2-sulfonic acid (2-phenyl-cyclopentyl)-amide (560 mg, 2.1 mmol, prepared in example 16) was dissolved in 10 mL of trifluoroacetic acid and 534 mg (6.3 mmol) of sodium nitrate was added. The reaction was stirred 5 hours at room temperature. The reaction was diluted with methylene chloride and washed with water and dilute sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated in vacuo to 620 mg of a crude yellow oil. This oil was purified by radial chromatography eluting with 98:2 methylene chloride:ethyl acetate to give 120 mg (18%) of the title compound as a white solid and also 400 mg (62%) which contained a small amount of ortho nitrated product. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][OH:21])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:4]=12)[CH3:2].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:23])[CH2:9][CH2:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])=[C:13]([CH3:22])[CH:12]=2)=[C:5]2[CH2:24][CH2:25][C:26]([CH3:28])([CH3:29])[CH2:27][C:4]=12)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(CCCO)c(C)c2)c2c1CC(C)(C)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)CCc2cc(C)c(CCCOS(C)(=O)=O)c(C)c2)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-[4-(3-hydroxy-propyl)-3,5-dimethyl-phenyl]-propan-1-one (135 mg, 0.328 mmol, Example 335) in DCM is treated with DIPEA (70 mg, 0.525 mmol) followed by methanesulfonylchloride (45 mg, 0.394 mmol). The mixture is stirred at rt for 1.5 h before it is diluted with DCM and washed with 0.5 M aq. citric acid solution followed by brine. The organic extract is dried over MgSO4, filtered and the solvent of the filtrate is evaporated to give methanesulfonic acid 3-{4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-2,6-dimethyl-phenyl}-propyl ester (165 mg) as a yellow resin; LC-MS: tR=1.20 min, [M+1]+=491.36.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][OH:37])=[CH:30][C:15]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2)=[O:17]>ClCCl.C(OCC)(=O)C>[Cl:13][C:14]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:15]=1[C:16]([NH:18][CH2:19][C:20]12[CH2:29][CH:24]3[CH2:23][CH:22]([CH2:28][CH:26]([CH2:25]3)[CH2:27]1)[CH2:21]2)=[O:17]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
Methanesulfonyl chloride (1.1 ml) and triethylamine (2 ml) were added to a solution of 2-chloro-5-(3-hydroxypropyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6d, 2.65 g) in dichloromethane at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted once with water, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the subtitled compound as an oil which slowly solidified (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(N)cc1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(N)cc1
Yield: 94 %

Procedure:
To a mixture of methyl 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxy late (500 mg, 1.61 mmol) in methanol (10 mL) and water (5 mL) was added a solution of sodium hydroxide (1100 mg, 27.4 mmol) in water (15 mL). The resultant mixture was heated for reflux until the complete of the reaction (monitored by thin layer chromatography). The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=1. The precipitates were collected by filtration to afford 2-(4-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a yellow solid, 430 mg, Yield 94%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:19][S:16]([CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]([F:20])([F:33])[F:32])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccccc3OC(F)(F)F)n2)c1

Procedure:
Example 7 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and [2-(trifluoromethoxy)phenyl]boronic acid (ABCR GmbH & CO. KG). The batch was purified by preparative HPLC:
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([OH:15])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:22][C:23]1([CH3:30])[NH:28][CH2:27][CH2:26][NH:25][C:24]1=[O:29].C(NCC)C.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.ClCCl>[C:1]([C:5]1[NH:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]([N:28]2[CH2:27][CH2:26][NH:25][C:24](=[O:29])[C:23]2([CH3:30])[CH3:22])=[O:15])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)c([N+](=O)[O-])[nH]1
Reactant: CC1(C)NCCNC1=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCNCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)N2CCNC(=O)C2(C)C)c([N+](=O)[O-])[nH]1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To 5-tert-butyl-2-nitro-1H-pyrrole-3-carboxylic acid (100 mg, 0.47 mmol) in benzene (2 mL) was added solid PCl5 (120 mg, 0.57 mmol). The resulting reaction mixture was stirred at RT until all the PCl5 went into the solution. This reaction mixture was then added to 3,3-dimethylpiperazin-2-one (120 mg, 0.94 mmol) and diethylamine (280 ml, 0.94 mmol) in dichloromethane (DCM) (3 mL). After 30 min, the reaction was diluted with DCM (10 mL) and followed by addition of sat. NaHCO3. The organic phase was then washed with 1N HCl and brine, dried, and concentrated in vacuo. This crude product was further purified using flash chromatography (EtOAc/Hexane: 1/4) to provide 4-(2-tert-butyl-5-nitro-1H-pyrrole-4-carbonyl)-3,3-dimethylpiperazin-2-one 6 (74 mg, 49%) as yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([CH2:12][CH2:13][CH2:14][N:8]3[CH2:7][C@@H:6]3[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@H:5]23)[CH:11]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]1([NH:1][C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([CH2:12][CH2:13][CH2:14][N:8]4[CH2:7][C@@H:6]4[CH2:15][NH:16][CH2:17][C@H:5]34)[CH:11]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@H]2C1
Reactant: Brc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1

Procedure:
A solution of (±)-cis-tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (0.08 g, 0.25 mmol), bromobenzene (0.04 g, 0.27 mmol), BINAP (0.001 g, 0.0015 mmol), sodium-t-butoxide, (0.06 g, 0.65 mmol) and Pd2DBA3 (0.0005 g, 0.0005 mmol) in 10 ml of degassed toluene was heated for 16 h at 90° C. The solution was cooled and filtered through a pad of silica gel and eluted with EtOAc. The volatiles were removed under reduced pressure to afford the title compound which was used without purification. LRMS (ES)+: 406.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1>>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: Clc1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(Cl)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.832 g of 1-(3-bromopropoxy)-3-chlorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[N:35]1([CH2:40][CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[N:51]2[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH:39]=[CH:38][N:37]=[CH:36]1>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:43]3[N:42]([CH2:41][CH2:40][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)[CH2:52][CH2:53]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: c1ccc2c(c1)nc(N1CCCNCC1)n2CCn1ccnc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCCN(c3nc4ccccc4n3CCn3ccnc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 66.1 using 1-(2-methoxy-5-(1h-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.40 g, 0.84 mmol) and 4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.48 g, 0.84 mmol) to give the title compound: Rf=0.18 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)C(=O)NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Product: CC(C)C(=O)NCc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)isobutyramide (0.125 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 14.5 mg of 147 following reverse phase HPLC purification. MS (Q1) 449.2 (M)+
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5](CC2C=CC=C(C(F)(F)F)C=2)[C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1.[Li+]>CO.Cl.[Pd]>[F:1][C@@H:2]1[CH2:6][NH:5][C@@H:4]([C:18]([NH:20][C@H:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[CH3:22])=[O:19])[CH2:3]1
Reactant: C[C@H](NC(=O)[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1)c1ccc(C(=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: [Li+]
Solvent: CO
Product: C[C@H](NC(=O)[C@H]1C[C@H](F)CN1)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A suspension of lithium 4-((S)-1-((2R,4S)-4-fluoro-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D161) (47 mg) and 10% w Pd/C (5 mg) in MeOH (5 ml) and 1M HCl (0.5 ml) was stirred under a constant current of H2 for 3 hrs. Catalyst was filtered off and solvent evaporated to afford a residue which was triturated with cHex and filtered to afford the title compound (D162) (22 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2=[N:9][C:10]3[CH2:16][CH2:15][CH2:14][C:11]=3[C:12](=[O:13])[N:7]2[CH:6]=[CH:5][CH:4]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>CO>[CH:17](=[C:16]1[C:10]2[N:9]=[C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][N:7]3[C:12](=[O:13])[C:11]=2[CH2:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccn2c(=O)c3c(nc12)CCC3
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccn2c(=O)c3c(nc12)C(=Cc1ccccc1)CC3

Procedure:
5-methoxy-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one, m.p. 212°-214° C., (4 g) was reacted with benzaldehyde (8 g) in methanol (150 ml) in the presence of sodium methoxide (4 g) at reflux temperature for 150 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and washed with water until neutral: crystallization from dioxane gave 2.5 g of 3-benzylidene-5-methoxy-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one, m.p. 229°-230° C., NMR (DMSO d6) δ ppm: 3.26 (bs) (4H, C-1 and C-2 protons), 4.20 (s) (3H, OCH3), 7.5-7.9 (m) (8H, =CH, C-6 and C-7 and phenyl protons), 8.90 (d.d) (1H, C-8 proton).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].NN>C(O)C>[NH2:24][CH2:23][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)c(Cl)c2)CC1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(CN)(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.2 %

Procedure:
To a solution of tert-butyl (7RS)-7-(3,4-dichlorophenyl)-7-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,4-oxazepane-4-carboxylate (1.39 g) in ethanol (14 ml) was added hydrazine (2.8 ml), and the mixture was stirred at room temperature for 14 hr. The precipitate was removed by filtration, and the solvent of the filtrate was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.9 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[CH:16]/[C:17]#[C:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)C>Cl>[Cl:25][C:23]1[CH:24]=[C:19]([C:18]#[C:17]/[CH:16]=[CH:15]/[CH2:14][OH:13])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Product: OC/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of diisobutylaluminium hydride (1.0 M solution in toluene, 20 mL, 20 mmol) at −78° C. was slowly added (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (1.1 g, 4.08 mmol). The reaction mixture was stirred for 2 h at −78° C., where after the reaction mixture was poured into hydrocloride acid (6N, 50 mL) and extracted with diethyl ether (3×40 mL) The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol in 750 mg yield.