Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=[O:5])[CH3:2].[CH3:23][O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[C:32](O)=[O:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([O:28][CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH:30]=2)[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CNC(C)C
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C

Procedure:
A mixture of (3S*,4R*)-4-(isopropylamino-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2.58 g, 8.2 mmol), 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid (1.93 g, 8.04 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (2.3 g, 9.02 mmol) and triethylamine (4.57 μL, 32.81 mmol) in CH2Cl2 (50 mL) is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with AcOEt. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude product is purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 50:50 to 0:100 and then AcOEt/MeOH 95:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.76 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:18][C:19]#[N:20])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CC#N)C1=O
Reaction time: 0.5 h
Yield: 70 %

Procedure:
[2-Oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (4.0 g, 20 mmol) is dissolved in THF (150 mL), cooled in an ice bath and treated with 60% sodium hydride (0.95 g, 24 mmol). The reaction mixture is stirred for 30 min., then treated with tetra-butylammonium iodide (0.16 g, 0.44 mmol) and bromoacetonitrile (1.7 mL, 24 mmol). After 3 h the reaction is quenched with water, concentrated to a small volume and extracted with methylene chloride (4×). The combined organic extracts are concentrated and the residue is chromatographed (2% MeOH/CH2Cl2) to give [1-cyanomethyl-2-oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (3.4 g 14 mmol). ). EI MS m/z: 240, [M+1]+; 1H NMR (CDCl3, 300 MHz) δ5.08 (br, 1H), 4.27 (m, 2H), 4.15 (m, 1H), 3.47 (m, 2H), 2.68 (m, 1H), 2.00 (m, 1H), 1.45 (s, 9H). This material (3.0 g, 12.6 mmol) is dissolved in ethanol (80 mL) and treated with platinum oxide (0.8 g) at 50 PSI of hydrogen gas for 24 h. The catalyst is removed by filtration and the solution is concentrated to yield the title compound (2.9 g, 12 mmol). EI MS m/z: 244, [M+1]+; 1H NMR (CDCl3, 300 MHz) δ5.13 (br, 1H), 4.13 (m, 1H), 3.34 (m, 5H), 2.85 (t, 1H), 2.60 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[NH:6][C@@H:7]1[CH2:19][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15](Br)=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].C[C:22]([N:24](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])=O.[Zn+2].C([O-])=O>[CH:1]([O:4][C:5](=[O:20])[NH:6][C@@H:7]1[CH2:19][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:22]#[N:24])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(Br)cc3c2C1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C[O-]
Product: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
((S)-7-Bromo-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (50 g, 148.27 mmol), zinc cyanide (10.45 g, 88.99 mmoles), and palladium (6.31 g, 2.96 mmol) are combined in dimethylacetamide (500 mL). The resulting slurry is sparged with sub-surface nitrogen for 10 min. Then 1,1′-bis(diphenylphosphino)ferrocene (3.29 g, 5.93 mmol) is added and the reaction is sparged for another 10 min. Finally, zinc formate (2.3 g, 14.80 mmol) is added and the reaction is sparged again for 10 min. The reaction is then placed under a nitrogen sweep and heated up to 110° C. overnight. The heat is turned off. The reaction is cooled to 85° C. and 3-mercaptopropyl-functionalized silica gel (5 g, 10 wt %) is added. The mixture is stirred for 2 h while cooling to room temperature. The reaction mixture is then filtered and the solid is rinsed with DMAC (50 mL). To the stirring orange filtrate is added 0.3 M ethylenediaminetetraacetic acid tetrasodium salt in water (1000 mL) over 10 min. The resulting slurry is stirred at room temperature and is filtered. The solid is rinsed with 0.3 M ethylenediaminetetraacetic acid tetrasodium salt (250 mL) followed by water (250 mL). A light brown solid is collected and dried overnight in the vacuum oven to provide the product (42.44 g) in quantitative yield.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12].[N:13]#[C:14][NH2:15]>C(O)C>[ClH:1].[NH:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[CH3:12])[C:14]([NH2:15])=[NH:13]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1NC(=N)N
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To 140 ml of ethanol, was added 22.6 g of 4-amino-3-methylbenzoic acid hydrochloride followed by 7.6 g of cyanamide. After having been stirred overnight at 60° C., the reaction mixture was freed from the solvent by distillation under reduced pressure and mixed with acetone to collect the crystals by filtration. The crystals were washed with acetone and recrystallized from a mixture of ethanol and ethyl acetate to obtain 8.9 g of white granular crystals of 4-guanidino-3-methylbenzoic acid hydrochloride.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([CH3:16])([CH3:15])[C@:5]([NH2:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH3:6].[CH3:18][NH:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=S>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:20]1[N:19]([CH3:18])[C:3](=[O:17])[C:4]([CH3:15])([CH3:16])[C@:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])([CH3:6])[N:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)C(C)(C)[C@](C)(N)c1ccccc1F
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2ccccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-phenyl)-2,2-dimethyl-butyric acid methyl ester and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester was obtained as a white solid. MS (ESI): m/z=364.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH3:21])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:26]4[CH:27]=[CH:28][C:23]([OH:22])=[CH:24][CH:25]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(O)cc3)CC2)cnn1C
Temperature: 25 °C
Yield: 85.6 %

Procedure:
Stir together 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (920 mg, 3.00 mmol), 4-(hydroxy)benzene boronic acid (497 mg, 3.6 mmol), potassium carbonate (996 mg, 7.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol) and water (6 mL) in N,N-dimethylacetamide (12 mL) at 120° C. for 5 hr. Cool to room temperature, add water (20 mL), extract with DCM (3×30 mL) and pass through an IST Phase Separator Frit®. Purify using SCX chromatography, eluting with 2.5 M ammonia in methanol and further purify using silica gel chromatography (eluting with 5:95 to 15:85 methanol:DCM). Concentrate and dry in a vacuum oven over night to give 4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenol as a light yellow powder (936 mg, 86%). MS (ES): m/z=365 [M+H].
Reaction SMILES: Cl[C:2]1[C:3](=[O:29])[N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21]C(=O)OC(C)(C)C)=[N:19][CH:20]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([CH2:14][N:4]2[C:5](=[O:13])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:3]2=[O:29])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cn1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccc(N)nc3)C2=O)cc1
Temperature: 150 °C
Yield: 29.6 %

Procedure:
To a solution of tert-butyl {5-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]pyridin-2-yl}carbamate (0.86 mmol, 357 mg) in dry DMF (1.0 mL) was added 4-methoxyaniline (0.96 mmol, 118 mg) and anhydrous potassium carbonate (0.96 mmol, 133 mg) and the reaction mixture was subjected to microwave heating single node at 150° C. for 15 min. The reaction mixture was purified using HPLC (95% 0.1M ammonium acetate buffer:5% CH3CN→5% 0.1M ammonium acetate buffer: 95% CH3CN, 10 min., 25 mL/min.) to give 102 mg (29%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.62 (dd, J=8.6 Hz, J=2.3 Hz, 1H), 7.21 (bs, 1H), 7.15-7.04 (m, 3H), 6.98-6.93 (m, 2H), 6.62-6.49 (m, 5H), 4.62 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: C(C1C=CC(O/[CH:10]=[CH:11]/[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=CC=1)(C)(C)C.I/C=C/OC1C=CC(C2C=CC=CC=2)=CC=1.[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cu]I>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][C:13]([O:12]/[CH:11]=[CH:10]/[S:49][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1ccc(O/C=C/Oc2ccc(-c3ccccc3)cc2)cc1
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: I/C=C/Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Product: C(=C/Sc1ccccc1)\Oc1ccc(-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
The compound 8 was prepared according to the general procedure described for the compound 6 above employing 4 (0.15 g, 0.47 mmol, 1 eq) and thiophenol (0.051 g, 0.05 mL, 0.47 mmol, 1 eq), Cs2CO3 (0.38 g, 1.2 mmol, 2.6 eq), CuI (0.044 g, 0.23 mmol, 0.49 eq) and L1 (0.042 g, 0.23 mmol, 0.49 eq) heating the reaction mixture at 60° C. for 10 h to give crude product, which was purified by silica gel column chromatography (100% hexane) to give compound 8, as white crystals (0.12 g, 90%). [When a mixture of Z and E-4 (1:9) was used as the starting material under same conditions at a temperature above 100° C. afforded a mixture of Z and E-8 (1:9). They were distinguished from each other by their coupling constants. Jcis=5.7 Hz while Jtrans=12 Hz (1H-NMR data of these mixtures are found below).] The characterization data below is that of 8 obtained from the reaction 4 with thiophenol: mp 92-96° C. 1H NMR (300 MHz, CD2Cl2): 7.66-7.54 (m, 4H, HAr), 7.48-7.40 (m, 2H, HAr), 7.37-7.28 (br s, 6H, HAr), 7.20-7.09 (m, 3H, HAr), 6.09-6.10 (d, 2H CH═CH, J=12.0 Hz) ppm; 13C NMR (300 MHz, CDCl3): 155.9, 150.6, 140.3, 137.5, 137.1, 128.9, 128.8, 128.5, 127.2, 127.0, 126.9, 125.7, 117.4, 102.1; IR (cm−1): 3054, 2985, 1659, 1624, 1599, 1515, 1485, 1265, 1233, 1185, 1174, 1112, 1086, 1025, 1007, 924, 839, 739, 407; HRMS (ESI) Calculated for C20H16OS [M+H]+ 305.1000. Found 305.0998. Elemental analysis Calculated for C20H16OS0.11 H2O: C, 78.40; H, 5.34. found: C, 78.40; H, 5.29.
Reaction SMILES: [CH:1]1(/[CH:4]=[C:5](/[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)\[N+:6]([O-])=O)[CH2:3][CH2:2]1>C1COCC1.[Ni]>[CH:1]1([CH2:4][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[NH2:6])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])/C(=C\C1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: NC(CC1CC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a room temperature solution of 4-(nitromethyl)-4′-(trifluoromethyl)biphenyl (200 mg, 0.711 mmol) and DBU (54.4 mg, 0.355 mmol) in DMF (3 ml) was added cyclopropanecarbaldehyde (99.7 mg, 1.42 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC to give impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (110 mg) as a colorless solid. To a solution of the impure (Z)-4-(2-cyclopropyl-1-nitrovinyl)-4′-(trifluoromethyl)biphenyl (55 mg, 0.16 mmol) in THF (3 mL) was added Raney nickel. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen (40 psi) overnight. The reaction mixture was purified by preparative TLC to give 2-cyclopropyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)ethanamine (20 mg) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.04-4.08 (m, 1H), 1.70-1.56 (m, 1H), 1.54-1.49 (m, 1H), 0.65-0.50 (m, 1H), 0.45-0.30 (m, 2H), 0.15-0.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[O:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22][O:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:4][C:3](=[O:16])[O:2][CH3:1])[CH:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)Oc1cc(O)c2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Temperature: 2 °C
Reaction time: 48 h
Yield: 75.4 %

Procedure:
4.62 g (21.2 mmol) of carbonic acid 4-hydroxy-naphthalen-2-yl ester methyl ester [Journal of Agricultural and Food Chemistry (1994), 42(12), 2970-2] was dissolved in 150 ml of MeCl2, 4.95 ml=4.71 g (25.4 mmol) of 2-(trimethylsilyl)-ethoxymethylchloride was added and this mixture cooled down to 2° C. 11.1 ml=8.38 g (63.5 mmol) of N-ethyl-diisoproylamine was added drop by drop and then, reaction was warmed up to ambient temperature. After 48 hours, it was poured into crashed ice and extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of n-heptane/MeCl2) to give 5.57 g of carbonic acid methyl ester 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yl ester as colorless oil.
Reaction SMILES: Cl.[NH:2]([C:4]1[C:5]([O:12][CH3:13])=[N:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1)[NH2:3].CC([O-])=O.[Na+].S(=O)(=O)(O)N.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[N:35]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39](=[O:43])[N:38]([CH3:44])[CH:37]=3)[C:34](=[O:45])[C:33](=O)[CH:32]2[C:47](=O)[CH2:48][CH3:49])=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CO>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[C:32]3[C:47]([CH2:48][CH3:49])=[N:3][N:2]([C:4]4[C:5]([O:12][CH3:13])=[N:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=4)[C:33]=3[C:34](=[O:45])[N:35]2[C:36]2[CH:41]=[C:40]([CH3:42])[C:39](=[O:43])[N:38]([CH3:44])[CH:37]=2)=[CH:27][CH:26]=1
Reactant: COc1ncc(NN)c(OC)n1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: CO
Product: CCc1nn(-c2cnc(OC)nc2OC)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 24.8 %

Procedure:
To a solution of 5-hydrazinyl-2,4-dimethoxypyrimidine hydrochloride (Step 46.8) (413 mg, 2 mmol) in MeOH (5 mL) were added NaOAc (123 mg, 1.5 mmol), sulfamic acid (99 mg, 1 mmol) and 5-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione (Step 60.1) (204 mg, 0.5 mmol) and the reaction mixture was stirred for 2.5 hr at 100° C. in the MW. The reaction mixture was added to a saturated aq. NaHCO3 solution and the aq. layer was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1) followed by preparative HPLC to afford, after crystallization from THF/Et2O, the title product (68 mg, 0.124 mmol, 25% yield) as a solid. tR: 1.03 min (LC-MS 2); ESI-MS: 521 [M+H]+ (LC-MS 2); Rf=0.36 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.8 Hz, 3H) 1.92 (s, 3H) 2.36 (m, 1H) 2.44 (m, 1H) 3.33 (s, 3H) 3.96 (s, 3H) 3.99 (s, 3H) 6.24 (m, 1H) 7.34 (m, 2H) 7.37-7.45 (m, 3H) 7.72 (s, 1H) 8.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH:22](O)[CH3:23]>>[Br:21][CH2:22][CH2:23][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Reactant: CC(O)Br
Product: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 68.8 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (1.01 g, 3.4 mmol) was reacted with bromoethanol (0.95 mL, 13.4 mmol) to afford 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.943 g, 69%) as white solid:
Reaction SMILES: [C:1]([CH2:5][N:6]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].C[O-].[Na+].[O:31]1[CH2:44][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>CO>[C:1]([CH2:5][N:6]1[CH2:17][CH2:16][N:15]([CH2:44][CH:32]([OH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CN1CCNCCN(CC(=O)OC)CCN(CC(=O)OC)CC1
Reactant: O=C(O)CCCCCCCCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1CCN(CC(=O)OC)CCN(CC(O)CCCCCCCCC(=O)O)CCN(CC(=O)OC)CC1

Procedure:
To a methanol solution of 1,4,7-tris-(carbomethoxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A methyl ester) is added 1.0 equivalent of freshly prepared anhydrous sodium methoxide and the solution is allowed to stir for several hours. To this solution is added one equivalent of 10,11-epoxyundecanoic acid and the solution is brought to reflux overnight. The solvent is removed in vacuo to give a crude hydroxyethylated product, 1,4,7-tris-(carbomethoxymethyl)-10-[2′-hydroxy-10′-carboxy(decyl)]-1,4,7,10-tetraazacyclododecane. Two to five equivalents of this product are dissolved in dimethylformamide (DMF) and corresponding equivalents of dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide are added with stirring overnight. To this solution is added one equivalent of generation 2 PAMAM and stirring is continued another 24 hours. The corresponding DO3A methyl ester conjugate is selectively hydrolyzed by treatment with aqueous sodium hydroxide in methanol. Treatment of the DO3A conjugate with excess Gadolinium(III) acetate (Gd(OAc)3) (buffered to pH=6) followed by incubation with excess diethylenetriaminepentaacetic acid (DTPA) and purification of the conjugate using preparative reverse phase HPLC gives a hydroxyethyl DO3A PAMAM starburst conjugate product which contains two to five equivalents of gadolinium which can not be removed by further challenges with excess DTPA.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].[F:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:16](=[O:18])[NH:26][CH2:25][CH2:24][C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: NCCc1ccc(F)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCCc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of N-Boc-L-phenylglycine (H, 17.2 g, 68.5 mmol) and (4-fluorobenzyl)methylamine (10.47 g, 75.3 mmol) in CH2Cl2 (550 mL) was cooled to 0° C. Disopropylethylamine (35.8 mL, 205 mmol) and PyBroP (38.3 g, 82.1 mmol) were then added sequentially. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the title compound (24.5 g, 96%) was isolated by chromatography on silica gel eluting with a gradient of 40% to 60% ethyl acetate in hexane. 1H NMR (selected signals, CDCl3): □6.02 (d, 0.3H), 5.56 (d, 0.7H), 2.83 (s, 0.9H), 2.78 (s, 2.1H), 1.40 (s, 6.3H, 1.39 (s, 2.7H).
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C:4](=[O:8])[NH:3]1.[C:9]1([CH2:15][CH2:16][C:17](Cl)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN1CCOCC1>C(OCC)(=O)C>[C:9]1([CH2:15][CH2:16][C:17]([N:3]2[C@@H:2]([CH3:1])[C:6](=[O:7])[O:5][C:4]2=[O:8])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)OC(=O)N1C(=O)CCc1ccccc1
Reaction time: 2 h
Yield: 55 %

Procedure:
(S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (345 mg, 3 mmol) was dissolved in ethyl acetate (20 mL), followed by the addition of 3-phenylpropanoyl chloride (658 mg, 3.9 mmol) under ice cooling. Further, a solution of N-methyl-morpholine (394 mg, 3.9 mmol) in ethyl acetate (10 mL) was added dropwise under ice cooling over 20 minutes, and the resulting mixture was then stirred at the same temperature for 2 hours. The reaction mixture was treated in a similar manner as in Synthesis Process 5 of Example 8 to afford the title compound (408 mg, 55%) as a colorless clear syrup.