Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([CH3:20])[C:7]=1[CH:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[O:18][CH:14]2[CH2:13][CH2:12]3)[C:9]1=[O:19].C(N(CC)CC)C.[C:34](Cl)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:19][C:9]1[CH:10]2[CH:15]([C:16](=[O:17])[C:8]=1[C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:5][C:6]=1[CH3:20])[CH:14]1[O:18][CH:11]2[CH2:12][CH2:13]1)=[O:39]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphenyl-4-yl)-10-oxa-tricyclo-[5.2.1.02,6]decane-3,5-dione (80 mg, 0.23 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (124 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphenyl-4-yl)-5-oxo-10-oxa-tricyclo[5.2.1.02,6]dec-3-en-3-yl 2,2-dimethylpropionate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.Cl.[CH3:15][O:16][C:17]1[NH:21][N:20]=[C:19]([NH2:22])[CH:18]=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:22][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=2)[NH:20][N:21]=1
Reactant: COc1cc(N)n[nH]1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Solvent: CCO
Product: COc1cc(Nc2cc(C(F)(F)F)nc(SC)n2)[nH]n1
Temperature: 90 °C
Yield: 21.5 %

Procedure:
To a solution of 4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (2.29 g) in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine hydrogen chloride salt (1.46 g). The resulting solution was heated at 90° C. for over night. The solvent was evaporated under reduced pressure. The crude compound was purified by Gilson (10-60% MeCN/H2O, 15 minutes) to give N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine as solid (0.64 g). m/z 306. N-(3-methoxy-1H-pyrazol-5-yl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine (240 mg) was dissolved in methylene chloride (5 mL), MCPBA (529 mg) was added. The resulting solution was stirred at room temperature for 0.5 hours and separate between methylene chloride and saturated sodium carbonate water solution. The organic layer was dried and solvent was removed under reduced pressure and low temperature. The crude product (270 mg) was carried on to do next step without further purification. m/z 338.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[Li]CCCC.CCCCCC.[B:26]([O-])([O-:28])[O-:27]>C1COCC1>[CH3:10][C:9]1([CH3:11])[C:4]2[CH:3]=[C:2]([B:26]([OH:28])[OH:27])[CH:14]=[CH:13][C:5]=2[NH:6][C:7](=[O:12])[O:8]1
Reactant: [O-]B([O-])[O-]
Reactant: CC1(C)OC(=O)Nc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (2 g, 7.8 mmol) in anhydrous THF (60 mL) was added a solution of n-BuLi in hexane (10 M, 2.4 mL, 24 mmol) at −78° C. under nitrogen. After stirring at −78° C. for 30 minutes, a slurry was obtained and treated with trisopropyl borate (6.5 mL, 28 mmol). The reaction medium was slowly warmed to ambient temperature and quenched with 1N aqueous hydrochloric acid solution (60 mL). Ethyl acetate (100 mL) was added and organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×60 mL). The combined organic layer was washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by a silica gel flash chromatography (ethyl acetate:hexane/2:1) to afford (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid as a white solid (1.4 g, 81%): mp 249-250° C.; 1H-NMR (DMSO-d6) δ10.21 (s, 1H, D2O exchangeable), 7.90-7.95 (br s, 2H, D2O exchangeable), 7.67 (m, 2H), 6.79 (d, 1H, J=7.8 Hz), 1.61 (s, 6H); MS (ESI) m/z 222 ([M+H]+, 87%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4].[CH:13]([NH2:16])([CH3:15])[CH3:14]>CCOC(C)=O>[CH:13]([NH:16][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[OH:4])([CH3:15])[CH3:14]
Reactant: CC(C)N
Reactant: OC(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)NCC(O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
A mixture of 3.9 g (14 mmol) 2-bromo-1-(3,4-dichlorophenyl)ethanol and 10 ml isopropylamine was sealed and heated to 80° C. for 16 h, then cooled to room temperature, diluted with 500 mL EtOAc, washed with 400 mL saturated aqueous NaHCO3, and 500 mL brine, then dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (5×8 cm silica gel, elute with 250 mL 3%MeOH/CH2Cl2, 100 mL 50% EtOH/CH2Cl2, then 200 mL EtOH) afforded 2.7 g 2-isopropylamino-1-(3,4-dichlorophenyl)ethanol. 1H NMR(400 mHz, CDCl3) 7.48 (d, 1H, J=1.92 Hz); 7.40 (d, 1H, J=8.22 Hz); 7.20 (dd, 1H, J=8.23and 1.92 Hz); 4.59 (dd, 1H, J=8.96 and 3.75 Hz); 2.94 (dd, 1H, J=12.2 and 3.66 Hz); 2.83 (sept, 1H, J=6.31 Hz); 2.57 (dd, 1H, J=12.3 and 8.87 Hz); 1.09 (d, 3H, J=6.31 Hz); 1.08 (d, 3H, J=6.22 Hz).
Reaction SMILES: C[O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[N+:16]([O-:18])=[O:17].[OH-].[Na+].O.Cl>CO>[N+:16]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1/[CH:5]=[CH:4]/[C:3]([OH:19])=[O:2])([O-:18])=[O:17]
Reactant: COC(=O)/C=C/c1ccc2ccccc2c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C=C/c1ccc2ccccc2c1[N+](=O)[O-]

Procedure:
(E)-3-(Nitronaphthalen-2-yl)-acrylic acid methyl ester (1.3 g, 5.05 mmol) was dissolved in MeOH (50 ml) and treated with 2N NaOH (3.8 ml; 7.6 mmol) and water (25 ml) for 1 hour at 50° C. The mixture was acidified with 2N HCl (4.2 ml; 8.33 mmol), water (100 ml) added and filtered to render the desired acid as yellow crystals (1.05 g; 80%).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8]1([C:14]([CH3:24])([CH3:23])[CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH:16]2O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:21][C@H:18]1[CH2:17][C@@H:16]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[C@H:15]([C:14]([CH3:24])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:23])[CH2:20][CH2:19]1
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Reactant: CCC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 2.28 g 2-oxobutyric acid (2, 22.11 mmol, 1.3 eq), 4.04 g (−)-8-phenylmenthol (18, 17.02 mmol, 1.0 eq) and 169.9 mg para-toluenesulfonic acid monohydrate (0.884 mmol, 0.52 eq) in 48 mL benzene was heated to reflux for 20 h 35 min. After cooling down to room temperature, the solution was washed twice with 50 mL saturated aqueous sodium hydrogencarbonate solution, and subsequently with 50 mL water and 50 mL brine. The organic phase was dried over 5 g sodium sulfate and was filtered. The filter cake was washed with 10 mL benzene. The organic phase was evaporated to dryness in a rotary evaporator (40° C., 20 mbar) yielding the title compound (4.98 g, 92% by weight) as colorless solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[N:5]1([CH2:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][NH2:23])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C1COCC1>[CH3:1][NH:2][C:3]([NH:23][NH:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][O:15][C:14]1[CH:24]=[CH:25][CH:26]=[C:12]([CH2:11][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:13]=1)=[O:21])=[O:4]
Reactant: CN=C=O
Reactant: NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Product: CNC(=O)NNC(=O)NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.8 ml (13 mmol) of methylisocyanate are added to 2.0 g (6.6 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]-propyl]-hydrazine carboxamide in 20 ml of THF and the reaction mixture is stirred at room temperature for one hour. The precipitate is filtered off and recrystallised from methanol. The analytical values are summarized in Table I.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[NH4+]>C(O)C.O>[C:26]1([S:23]([C:17]2[C:16]3[C:20](=[CH:21][CH:22]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:15]=3)[NH:19][CH:18]=2)(=[O:24])=[O:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]cc(S(=O)(=O)c4ccccc4)c3c2)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(N3CCNCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
4-(3-Benzenesulfonyl-1H-indol-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 1.13 mmol) was dissolved in 5 mL of ethanol and 3 mL of conc. hydrochloric acid were added. The mixture was heated to a gentle boil for 2-3 min, cooled to room temperature, basified with ammonium hydroxide, and diluted with 20 mL of water. After the mixture was allowed to stand overnight, the solid was filtered, washed with water and dried to give 0.37 g of 3-benzenesulfonyl-5-piperazin-1-yl-1H-indole (201) as a tan crystalline solid, m.p. 254-264° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:14](Cl)(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:6]([NH:7][C:14](=[O:16])[CH3:15])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cn(-c2cccnc2)nc1Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cn(-c2cccnc2)nc1Cl

Procedure:
In step g of Scheme 1, 3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-amine (5d) is acylated with acetylating agents such as acetyl chloride or acetic anhydride, preferably acetic anhydride (Ac2O) to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c). The acylation is conducted in the presence of a base, preferably an inorganic base, such as, sodium bicarbonate (NaHCO3), and preferably, a polar solvent, such as ethyl acetate and/or tetrahydrofuran. This reaction may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: C([C:3]([N:17]1CCOCC1)([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)#N.CC(CC(=O)C1C=C[N:34]=[CH:33]C=1)C(OC)=O>>[CH3:33][N:34]1[C:6](=[O:8])[CH:5]([CH3:10])[CH2:4][C:3]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[N:17]1
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Reactant: COC(=O)C(C)CC(=O)c1ccncc1
Product: CC1CC(c2ccncc2)=NN(C)C1=O

Procedure:
Following the procedure described in Example A-16 but using in place of methyl 4-cyano-4-(4-morpholinyl)-4-(4-pyridinyl)-2-methylbutanoate a molar equivalent quantity of methyl 2-methyl-4-oxo-4-(4-pyridinyl)butanoate, it is contemplated that there can be obtained 4,5-dihydro-2,4-dimethyl-6-(4-pyridinyl)-3(2H)-pyridazinone. Also, this same compound can be obtained following the procedure described in Example A-1 but using in place of 4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of 2-methyl-4-oxo-4-(4-pyridinyl)butanenitrile.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1ccncc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccncc4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and pyridin-4-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(pyridin-4-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.51 mg, 10%). 1H-NMR (MeOD): 2.50 (t, 1H), 2.64 (dd, 1H), 3.37 (s, 3H), 5.91 (d, 1H), 7.26 (d, 1H), 7.45 (m, 5H), 7.82 (d, 1H), 7.94 (t, 1H), 8.16 (s, 2H), 8.71 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[C:19](=[O:22])[C:18]([CH3:24])([CH3:23])[CH2:17][N:16]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:30]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)C(=O)C1C=CC=CC=1O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:53][NH:54][CH2:55][CH2:56][N:57]([CH3:59])[CH3:58]>CN(C=O)C.C(OCC)(=O)C.O.[OH-].[NH4+].[Cu]I>[CH:25]1([N:16]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19](=[O:22])[N:20]([CH3:21])[C:14]3[CH:13]=[N:12][C:11]([NH:10][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([N:54]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[CH3:53])=[CH:3][CH:4]=4)[CH3:9])=[N:30][C:15]2=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNCCN(C)C
Reactant: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CCN(CC)C(=O)c1ccccc1O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C)c1ccc(N(C)CCN(C)C)cc1
Temperature: 90 °C
Yield: 17.9 %

Procedure:
Into an oven dried Schlenk tube dried under Argon was added (S)-2-(1-(4-bromophenyl)ethylamino)-9-cyclopentyl-5,7,7-trimethyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.2096 mmol), CuI (1.996 mg, 0.01048 mmol), N,N-diethyl-2-hydroxy-benzamide (8.101 mg, 0.04192 mmol) and K3PO4 (88.98 mg, 0.4192 mmol). The tube was evacuated and re-filled with Argon (three times), and N,N′,N′-trimethylethane-1,2-diamine (32.12 mg, 40.87 μL, 0.3144 mmol) in DMF (1 mL) was added and the reaction mixture was heated to 90° C. for 96 h. Additional CuI (1.996 mg, 0.01048 mmol), N,N-diethyl-2-hydroxy-benzamide (8.101 mg, 0.04192 mmol) and N,N′,N′-trimethylethane-1,2-diamine (214.2 mg, 272.5 μL, 2.096 mmol) were added to the tube and the tube was re-charged with argon and heated to 90° C. overnight. The reaction mixture was then cooled to the ambient temperature and diluted with ethyl acetate (5 mL), water (5 mL) and ammonium hydroxide (0.2 mL). The aqueous layer was extracted with ethyl acetate (four times, 5 mL each), dried with MgSO4, filtered and concentrated in vacuo. The crude product was purified by mass directed HPLC and product fractions combined and passed through a bicarbonate cartridge and lyophilized to give the title compound as a white solid (18.5 mg, 17% yield).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[O:11]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:12][C:10]([N:9]([CH3:13])[CH3:8])=[O:11])=[O:4]
Reactant: CN(C)C(N)=O
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NC(=O)C(C)(C)Br
Reaction time: 4 h

Procedure:
2-Bromo-2-methylpropionyl bromide (8.9 g) in dichloromethane (20 ml) was added dropwise at 0° to a stirred suspension of 1,1-dimethylurea (3.4 g) in dichloromethane (25 ml) and triethylamine (16 ml). The mixture was stirred for 4 hr. at 22° and the solvent was evaporated. The residue was stirred with saturated sodium hydrogen carbonate solution (40 ml) and extracted with ethyl acetate (3×20 ml). The ethyl acetate solution was dried and evaporated. The residue was stirred with light petroleum (b.p. 40°-60°, 50 ml) and the remaining solid was filtered off and suspended in sodium hydrogen carbonate solution and extracted into ethyl acetate (2×20 ml). The ethyl acetate solution was dried and evaporated, leaving the urea as a pale brown solid, 1.4 g, m.p. 98°-100°, max (Nujol) 3400, 3370 (NH), 1742, 1685 cm-1 (--CONH.CON--), τ (DMSO d6) 8.06 (--C(Me)2), 7.01 (-N(Me)2), 1.6 (--CONHCO--).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+:13].[OH-]>O>[NH2:13][CH2:12][C@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: [OH-]
Solvent: O
Product: NC[C@H](O)COCc1ccccc1
Yield: 98 %

Procedure:
ER-886133 and ER-886134: A solution of (S)-2-((benzyloxy)methyl)oxirane (65 g, 0.396 mol) and 28% NH4OH in water was stirred at rt for 14 h after which time the completed reaction was concentrated and azeotroped two times with toluene (150 mL each) to obtained (S)-1-amino-3-(benzyloxy)propan-2-ol (70.6 g, 0.390 mol, 98% yield) as a crude white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:34]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][C@@H:48]([C:57]([OH:59])=O)[NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[NH2:60][CH2:61][CH:62]([OH:65])[CH2:63][OH:64]>CN(C=O)C>[CH2:34]([O:41][C:42](=[O:43])[NH:44][CH2:45][CH2:46][CH2:47][C@H:48]([NH:49][C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[C:57]([NH:60][CH2:61][CH:62]([OH:65])[CH2:63][OH:64])=[O:59])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: NCC(O)CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[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: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCC(O)CO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
658.5 mg (1.8 mmol) of HATU and 129.2 mg (1 mmol) of N,N-diisopropylethylamine are added to a solution of 366 mg (1 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 182.2 mg (1 mmol) of 3-aminopropane-1,2-diol are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:73]=[CH:72][C:7]([CH2:8][CH:9]([N:22](S(C2C=CC=CC=2C)(=O)=O)[CH2:23][CH2:24][N:25](S(C2C=CC=CC=2C)(=O)=O)[CH2:26][CH2:27][N:28](S(C2C=CC=CC=2C)(=O)=O)[CH2:29][CH2:30][NH:31]S(C2C=CC=CC=2C)(=O)=O)COS(C2C=CC=CC=2C)(=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2]>CN(C=O)C>[N+:1]([C:4]1[CH:73]=[CH:72][C:7]([CH:8]2[CH2:9][NH:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][NH:31]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1S(=O)(=O)NCCN(CCN(CCN(C(COS(=O)(=O)c1ccccc1C)Cc1ccc([N+](=O)[O-])cc1)S(=O)(=O)c1ccccc1C)S(=O)(=O)c1ccccc1C)S(=O)(=O)c1ccccc1C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CNCCNCCNCCN2)cc1

Procedure:
The intramolecular cyclization step undertaken to give 2-(p-nitrobenzyl)-N,N',N", N"'-tetrakis (tolylsulfonyl)-1,4,7,10-tetraazacyclododecane is performed by treating 2-(p-nitrobenzyl)-N,N',N",N"',O-pentakis(tolylsulfonyl)-3,6,9,12-tetraaz-adodecanol with 1 equivalent of CsCO3 in DMF under high dilution conditions (0.01M of 2-(p-nitrobenzyl)-N,N',N",N"',O-pentakis(tolylsulfonyl)-3,6,9,12-tetraaza-dodecanol) at 60° C. for 5 hours under nitrogen. The tosyl protecting groups of 2-(p-nitrobenzyl)-N,N',N",N"'-tetrakis (tolylsulfonyl)-1,4,7,10-tetraazacyclododecane are removed using concentrated H2SO4 at 100° C. for 56 hours, affording 2-(p-nitrophenyl)-1,4,7,10-tetraaza-cyclododecane. 2-(p-nitrophenyl)-1,4,7,10-tetraaza-cyclododecane is treated with 4.4 equivalents of bromoacetic acid in water at pH 10 at 70° C. for one day to give crude product. The product p-nitrobenzyl-DOTA is obtained after anion-exchange column chromatography with elution of increasing concentration of ammonium acetate, for example.
Reaction SMILES: II.[CH3:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH3:15])[C:8]3[CH2:22][CH2:23][N:24]([C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27])[CH2:25][C:7]=3[C:6]=2[CH:5]=1.[CH2:34](I)I>C1COCC1.[Cu].[Zn]>[CH3:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][N:19]([CH3:34])[CH2:20][CH:21]=3)[CH3:15])[C:8]3[CH2:22][CH2:23][N:24]([C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27])[CH2:25][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC(=Cn1c2c(c3cc(C)ccc31)CN(C(=O)OCC(Cl)(Cl)Cl)CC2)c1ccncc1
Reactant: ICI
Agent: [Cu]
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(=Cn1c2c(c3cc(C)ccc31)CN(C(=O)OCC(Cl)(Cl)Cl)CC2)C1=CCN(C)C=C1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
Zinc-copper couple (800 mg) was dissolved in THF and a crystal of iodine was added. The reaction mixture was stirred at 85° C. until the brown color disappeared. A mixture of 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (400 mg, 0.83 mmol) and methylene iodide (447 mg, 1.67 mmol) was added at the same temperature and the mixture was heated at 85° C. overnight. The reaction mixture was filtered under vacuum and the filtrate purified by reverse phase HPLC to obtain 2,2,2-trichloroethyl 3,4-dihydro-8-methyl-5-(2-(N-methyl-pyridin-4-yl)prop-1-enyl)-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (130 mg TFA salt). To the purified compound (130 mg) was added acetic acid (2 mL) and zinc dust (35 mg). The reaction mixture was stirred at RT for 2 days. MeOH (10 mL) was added and the mixture filtered under vacuum. The filtrate residue was washed with additional MeOH (2×10 mL) and concentrated under reduced pressure. The product obtained was purified on reverse phase chromatography. Yield: 25 mg (TFA salt). 1H NMR (CD3OD, TFA salt): δ (ppm): 8.8 (d, 2H), 8.3 (d, 2H), 7.8 (s, 1H), 7.4 (s, 1H), 7.1 (s, 2H), 4.5 (s, 2H), 4.4 (s, 3H), 3.6 (bs, 2H), 3.1 (bs, 2H), 2.4 (s, 3H), 2.2 (s, 3H).