Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>C1(C)C=CC=CC=1>[CH3:6][CH:5]([CH3:7])[CH2:4][C:3](=[O:8])[CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)CC(=O)CBr
Agent: [K]
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 23.9 %

Procedure:
Dissolve 1-bromo-4-methyl-2-pentanone (11.0 g, 61.4 mmol) and potassium phthalimide (11.9 g, 64.5 mmol) in toluene (60 mL) at room temperature under a nitrogen atmosphere. Heat the mixture to 100° C. and stir for 16 h. Cool the resulting slurry to room temperature, filter off solids, and concentrate the filtrate in vacuo to a solid. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/EtOAc (1:1) to obtain the desired intermediate (3.6 g, 24%). MS (ES+) m/z: 246.3 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]([NH:23][NH2:24])=[O:22])[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:41]#[C:42]Br>O.O1CCOCC1>[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]3[O:22][C:42]([NH2:41])=[N:24][N:23]=3)[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
A solution of sodium bicarbonate (10.0 mg, 0.12 mmol) in water (267 μL) was added dropwise via syringe to a stirred solution of 4d (0.108 mmol) in dioxane (1.0 mL) at room temperature. A suspension of cyanogen bromide (13.0 mg, 0.12 mmol) in dioxane (120 μL) was added in 4 equal portions at 1 minute intervals. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TiFA as modifier). Lyophilization of the purified fractions afforded the title compound 5b, m/z (ES) 489 (MH)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14](=O)[C:8]=2[CH:7]=[CH:6][N:5]=1>C(N(CC)CC)C>[OH:3][N:2]=[C:14]1[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]1
Reactant: O=c1ccccc2cnccc12
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: ON=c1ccccc2cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Hydroxylamine hydrochloride (2.20 g, 0.317 mole) was added to a stirred mixture of cyclohepta[1,2-c]pyridin5-one and triethylamine (15.00 ml) and the resulting yellow solution was stirred overnight at its reflux temperature. The pale yellow solution was cooled to room temperature, then concentrated by solvent evaporation to a pasty yellow solid. The solid was dissolved in a mixture of water and diethyl ether (1:1, ~700ml) and the yellow Et2O layer was separated and extracted with water (2X, 500 ml), washed with brine, then dried (MgSO4). Filtration through celite followed by concentration of the filtrate gave 2.30g (53%) of a yellow solid, which after trituration with hexane and recrystallization from aqueous ethanol, gave the desired product, m.p. 164°-167° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25](=O)[C@@H:26]([NH:29][C:30]2[N:38]=[CH:37][N:36]=[C:35]3[C:31]=2[N:32]=[CH:33][N:34]3C2CCCCO2)[CH2:27][CH3:28])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][O:17]C(=O)C(C)(C)C)[CH2:10]2)[CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:24]=[C:25]([C@@H:26]([NH:29][C:30]3[N:38]=[CH:37][N:36]=[C:35]4[C:31]=3[N:32]=[CH:33][NH:34]4)[CH2:27][CH3:28])[N:8]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][OH:17])[CH2:10]3)[C:6]=2[CH:7]=1
Reactant: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Agent: Cl
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1[C@@H]1CCCN(CCO)C1
Temperature: 25 °C
Yield: 24.7 %

Procedure:
A solution of 2,2-dimethylpropionic acid 2-[(R)-3-(5-fluoro-2-{(S)-2-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]butyrylamino}phenylamino)piperidin-1-yl]ethyl ester (258 mg, 0.41 mmol), in aqueous 6M HCl (3 mL) was refluxed for 40 min. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (C18, gradient 2-30% MeOH in 0.5% TFA/H2O) then loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane, then 2M NH3/MeOH. Further purification by column chromatography (Si—PCC, gradient 3-21% 2M NH3/MeOH in DCM) afforded a colourless solid. The preparation was repeated on the same scale to give a combined yield of 44.4 mg of 259 (12%). LCMS (Method K): RT 2.07 min [M+H]+ 439.1. 1H NMR (CD3OD, 400 MHz): δ 8.28 (1H, s), 8.09 (1H, s), 7.59 (1H, dd, J=8.9, 5.0 Hz), 7.50 (1H, dd, J=9.6, 2.3 Hz), 7.00 (1H, dt, J=9.2, 2.3 Hz), 5.84 (1H, bs), 5.04-4.94 (1H, m), 3.68 (2H, t, J=5.8 Hz), 3.12-3.08 (1H, m), 3.00-2.93 (2H, m), 2.71-2.57 (2H, m), 2.33-2.16 (4H, m), 1.89-1.86 (1H, m), 1.82-1.77 (1H, m), 1.62-1.51 (1H, m), 1.09 (3H, t, J=7.4 Hz)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[C:16]([NH:24][C@H:25]([C:30](O)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(Cl)Cl.CCN(CC)CC>[C:16]([NH:24][C@H:25]([C:30]([NH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:31])[CH2:26][CH:27]([CH3:28])[CH3:29])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCC1CCCN1Cc1ccc(Cl)cc1
Reactant: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1ccccc1)C(=O)NCC1CCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mmol) in CHCl3 (1 mL) was treated with EDCI (23 mg), HOBt (16.2 mg) and Et3N (15.2 μL), and stirred at 25° C. for 16 h. The reaction mixture was diluted with CH2Cl2 (0.5 mL), washed with 2 N aqueous NaOH solution (2×0.75 mL), dried by filtration through a PTFE membrane and concentrated to afford 2-((N-benzoylleucyl)aminomethyl}-1-(4-chlorobenzyl)pyrrolidine (compound No. 344) (74 mg, quant): The purity was determined by RPLC/MS (85%); ESI/MS m/e 442 (M++H, C25H32ClN3O2).
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:39][C@@H:40]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:41]([N:43]([C@@H:55]([CH3:63])[CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)=[O:42]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:39][C@@H:40]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:41]([N:43]([C@@H:55]([CH3:63])[CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 182 mg (0.77 mmol), hydroxybenzotriazole 104 mg (0.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 148 mg (0.77 mmol) in dichloromethane 3 ml, a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 260 mg (0.51 mmol) and 4-dimethylaminopyridine 31 mg (0.26 mmol) in dichloromethane 3 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound 333 mg (90%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:25])[C:6]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH3:25][C:7]1[C:6]2[CH:26]=[C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:3]=[CH:4][C:5]=2[S:9][C:8]=1[S:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:12])=[O:11]
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N4CCOCC4)cc3c2C)c1
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-{[(5-bromo-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate (Intermediate 18) (23 mg, 0.05 mmol), morpholine (9 mg, 0.10 mmol), PdOAc2 (0.6 mg, 0.0025 mmol), 2-(di-tbutylphosphino)biphenyl (1 mg, 0.0035 mmol) and Cs2CO3 (66 mg, 0.25 mmol) in dioxane (200 μL) was heated at 110° C. for 20 h giving the intermediate ethyl 3-{[(3-methyl-5-morpholin-4-yl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate. The intermediate ester was hydrolyzed using LiOH in aqueous THF (1 mL, 1:1 water/THF) giving the title compound. MS (ESI+) calcd mass for C20H20N2O5S2 432.081363, found 432.081153.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:22]=[CH:21][C:20]=2[NH2:34])=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:36]=[CH:35][C:17]([O:18][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:22]=[CH:21][C:20]=2[NH:34][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Oc3ccc(C#N)cc3)c2)cc1
Yield: 68.7 %

Procedure:
4-Fluorobenzene sulfonyl chloride (0.126 g, 0.65 mmol) was added to a stirred solution of 1,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with other reagents as mentioned in Example 20(c) to afford 0.18 g of the required product. 1H NMR (DMSO-d6): δ 6.86 (1H, brs), 6.95 (3H, m), 7.26 (2H, d), 7.34 (1H, d), 7.54 (3H, t), 7.82 (2H, d), 7.95 (2H, d), 7.95 (2H, m).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:31](OC)=[O:32])[NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:31][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OC[C@H](COCc1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
Methyl O-benzyl-N-trityl-L-serinate (2.94 g, 6.52 mmol) was dissolved in 100 mL of anhydrous Et2O and the solution was cooled to 0° C. under N2. Lithium aluminum hydride (1.63 g, 42.9 mmol) was added and the mixture was stirred for 90 minutes. The reaction mixture was then sequentially treated with 1.63 mL of H2O, 1.63 mL of 15% NaOH solution and 4.90 mL of H2O. After stirring for 30 minutes, the reaction mixture was filtered to remove the white solid. The solid was washed with several portions of Et2O and the combined filtrates were concentrated under reduced pressure. Chromatography (SiO2, 15-20% ethyl acetate/hexanes) gave 2.78 g of (2R)-3-(benzyloxy)-2-(tritylamino)propan-1-ol as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.[CH:35]([S:37]([CH:40]=C)(=[O:39])=[O:38])=[CH2:36].Cl.C(OCC)C>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: C=CS(=O)(=O)C=C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 152, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with vinyl sulfone. The crude product was dissolved in DCM and treated with 4N HCl. After stirring for 10 min diethyl ether was added and the solid precipitate collected by filtration to give 175 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 10.63 (s, 1 H); 8.45 (s, 1 H); 8.30 (s, 1 H); 7.85 (td, J=8.75, 5.90 Hz, 1 H); 7.72 (t, J=9.62 Hz, 1 H); 7.42 (t, J=8.57 Hz, 1 H); 7.22 (d, J=2.33 Hz, 1 H); 7.11 (dd, J=8.45, 2.37 Hz, 1 H); 6.97 (d, J=8.34 Hz, 1 H); 4.22 (t, J=5.02 Hz, 2 H); 3.82 (t, J=7.50 Hz, 2 H); 3.76-3.63 (m, 2H); 3.59 (d, J=9.30 Hz, 2 H); 3.16 (s, 3 H); 3.14 (m, 2 H); 3.06 (t, J=5.04 Hz, 2 H); 2.66 (s, 1 H); 1.96-1.76 (m, 4 H). LCMS: RT=7.54 min, M+H+=555
Reaction SMILES: [C:1]12([CH2:11][NH:12][CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CO.O=[Pt]=O>[CH:16]1([C@H:14]([OH:15])[CH2:13][NH:12][CH2:11][C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: O[C@H](CNCC12CC3CC(CC(C3)C1)C2)C1CCCCC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of (S)-2-((1-adamantylmethyl)amino)-1-phenylethanol (50 mg, 0.18 mmol) in dry CH3OH (5 mL) was added PtO2 (10 mg) as the catalyst. The mixture was stirred under hydrogen (55 psi) at 60-70° C. overnight. After filtration, the filtrate was evaporated to give a residue, which was purified by preparative TLC to give (S)-1-cyclohexyl-2-((1-adamantylmethyl)amino)ethanol (20 mg, 40%). 1H NMR (MeOD, 400 MHZ): δ=1.07-1.99 (m, 25H), 2.35-2.51 (q, 2H), 2.63 (t, 1H), 2.80 (d, 1H), 3.51 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][O:33]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][O:33]4)=[CH:29][C:22]=3[O:21][CH3:20])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(=O)CC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: COc1cc(OCC2CCCO2)ccc1C=O
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCNCC1
Product: COc1cc(OCC2CCCO2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Temperature: 70 °C
Yield: 26.9 %

Procedure:
In a 20 mL reaction vessel were placed 19.3 mg (85.0 μmol) of 6-(1H-indol-6-yl)hex-5-ene-2,4-dione and 22 mg (0.32 mol) of boron oxide and they were dissolved in 0.4 mL of ethyl acetate. To the mixture under stirring at 70° C., 20 mg (85 μmol) of 2-methoxy-4-(2-tetrahydrofuranylmethoxy)benzaldehyde and 32 μL (0.14 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, 18 μL (0.18 mmol) of piperidine was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (2 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 10.2 mg (27% yield) of the title compound as an orange powder with the following properties.
Reaction SMILES: F[C:2]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:3]=1[C:4]([C:6](=[CH:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:26][C:23]1[CH:22]=[C:3]2[C:2](=[CH:25][CH:24]=1)[N:13]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC(=O)C(=CNCCN1CCOCC1)C(=O)c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCN2CCOCC2)c2ccc(I)cc2c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 2-(2-fluoro-5-iodobenzoyl)-3-(2-morpholinoethylamino)acrylate (Intermediate 23, 358 mg, 0.75 mmol) and potassium carbonate (208 mg, 1.50 mmol) in DMF (7 mL) was heated to 100° C. for 4 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The solid that formed was placed under high vacuum overnight (328 mg) to yield the desired product. MS (ESP): 457 (M+H+) for C18H21IN2O4; NMR: 1.28 (t, J=7 Hz, 3H), 2.43 (m, 4H), 2.61 (m, 2H), 3.50 (m, 4H), 4.22 (q, J=7 Hz, 2H), 4.46 (m, 2H), 7.67 (d, J=9 Hz, 1H), 8.05 (m, 1H), 8.50 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=S)[C:8]3([CH2:11][NH:12][C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:16]([CH3:17])=[N:19][N:20]=[C:7]3[C:8]3([CH2:10][CH2:9]3)[CH2:11][NH:12][C:4]=2[CH:3]=1
Reactant: S=C1Nc2ccc(Br)cc2NCC12CC2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)cc1NCC21CC1
Yield: 52.9 %

Procedure:
A solution of 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropane]-2(1H)-thione (500 mg, 1.77 mmol) and acetohydrazide (1.05 g, 14.2 mmol) in n-butanol (15 mL) was heated to 130° C., and maintained at the same temperature for 12 hours. The reaction mixture was concentrated, extracted with ethyl acetate (15 mL), washed with water (25 mL*2). The organic phase was separated, dried by sodium sulfate, filtered and concentrated to give the crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=30:1) to afford 8-bromo-1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (286 mg, 53%). 1H NMR (300 MHz, d6-DMSO): δ 7.31-7.28 (m, 2H), 7.11 (dd, J=6.0 Hz, J=2.4 Hz, 1H), 5.80-5.78 (m, 1H), 3.36-3.35 (m, 2H), 2.37 (s, 3H), 0.88-0.86 (m, 2H), 0.77-0.73 (m, 2H). LRMS (M+H)+: calcd 304.03. found 304.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].Br[CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([O:8][CH3:9])=[O:7]>C(#N)C>[N:1]([CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:16]([O:18][CH3:19])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Solvent: CC#N
Product: COC(=O)CCCCCCC(N=[N+]=[N-])C(=O)OC
Yield: 99.1 %

Procedure:
Soldium azide (4.87 g, 75 mmol) was added to a solution of dimethyl 2-bromoazelate (5.9 g, 20 mmol) prepared according to Auguston, M, et al; Acta Chim. Acad. Sci. Hung; 46:85 (1965) in acetonitrile, and the mixture was heated at reflux temperature for 4 h. The solvent was removed in vacuo, dichloromethane (80 ml) was added to the residue, and the mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as an oil (5.1 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([CH:9]=O)[N:8]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[NH:12][NH2:13]>>[CH2:16]([O:15][C:11](=[O:14])[NH:12][N:13]=[CH:9][C:7]1[N:8]=[C:4]([CH2:3][O:2][CH3:1])[NH:5][CH:6]=1)[CH3:17]
Reactant: COCc1nc(C=O)c[nH]1
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1c[nH]c(COC)n1

Procedure:
A 19.60 gm. portion of 2-(methoxymethyl)-4-imidazolecarboxaldehyde and 16.02 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 186°-190° C.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O.[H][H]>C1([C@@H]2CC[C@@H](C3C=CC=CC=3)P2C2C(=O)OC(=O)C=2P2[C@H](C3C=CC=CC=3)CC[C@H]2C2C=CC=CC=2)C=CC=CC=1.F[B-](F)(F)F.[Rh+].C1CCC=CCCC=1.CO>[CH3:11][O:10][C:1](=[O:9])[C@@H:2]([CH3:3])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: [H][H]
Agent: [Rh+]
Agent: F[B-](F)(F)F
Agent: O=C1OC(=O)C(P2[C@H](c3ccccc3)CC[C@H]2c2ccccc2)=C1P1[C@H](c2ccccc2)CC[C@H]1c1ccccc1
Solvent: C1=CCCC=CCC1
Solvent: CO
Product: COC(=O)C[C@H](C)C(=O)OC
Temperature: 25 °C

Procedure:
The reaction was carried out in an Argonaut Endeavor hydrogenation vessel. The glass liner was charged with dimethyl itaconate (316 mg, 2.0 mmol) and 3,4-bis[(S,S)-2,5-diphenyl-phospholan-1-yl]-furan-2,5-dione-(1,5-cyclooctadiene) rhodium(I) tetrafluoroborate (1.7 mg, 0.002 mmol, S/C 1000). The vessel was charged to 10 bar nitrogen and vented (×5). Degassed methanol (4 ml) was added. The vessel was charged to 10 bar nitrogen and vented (×2). Stirring was commenced at 1000 rpm and the contents were heated to 25° C. The vessel was charged to 10 bar hydrogen. Hydrogen uptake was complete after 16 h. The mixture was vented and evaporated to give (S)-2-methylsuccinic acid dimethyl ester, conversion 100%, ee 96.6% (Chiraldex GTA, 30 m×0.25 mm, injector/detector 180° C., helium 14 psi, 90° C. for 6 min then ramp at 1° C./min to 105° C., retention times S 10.11 minutes, R 10.48 minutes). In comparison, much lower enantioselectivity, of 60.2% ee, is reported by Holz, J. et al, ibid., for the same transformation, at S/C 100 in methanol, catalysed by the corresponding rhodium complex of Me-Malphos [i.e. the analogue of ligand (7) with Me groups at the 2- and 5-position of each phospholane ring]. Holz, J. et al also report that a change of solvent, to THF, increases the enantioselectivity to 86% ee but this still falls short of the 96.6% ee achieved in the current example at a higher S/C ratio.