Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C@:22]1([CH3:28])[CH2:26][O:25]C(=O)[NH:23]1)[CH:16]=[CH:15]2.C(O)C.O.[OH-].[Li+].O>>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH:2]3[CH2:3][CH2:4][CH:5]4[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]4)[CH2:1]3)[CH:13]=2)[CH:18]=1)([CH3:28])[CH2:26][OH:25]
Reactant: C[C@@]1(c2ccc3cc(OC4CCC5CCCCC5C4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(OC3CCC4CCCCC4C3)ccc2c1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
(R)-4-[6-(Decahydro-naphthalen-2-yloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol) was dissolved in ethanol (2.2 g, 0.049 mol) and treated with 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol). The mixture was then heated to 80° C. overnight. The reaction was then cooled to room temperature and quenched with 1 N HCl. The reaction was then diluted with water and white solid formed. Solid was removed via filtration and dried overnight on filter to give 4 mg the desired product as a white solid (2%). ESI-MS: 337 (M−16)+. 1H NMR (400 MHz, DMSO-d6) δ=7.11-6.92 (m, 3H), 6.75-6.64 (m, 1H), 6.48-6.29 (m, 2H), 3.74-3.58 (m, 1H), 3.20-2.95 (m, 2 H), 1.21-0.96 (s, 22H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=[CH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.Br.N1(C(N2C3C=CC=CC=3C=CC3C=CC=CC2=3)=O)CCNCC1.C1(=O)[O:64][C:62](=[O:63])[CH2:61][CH2:60][CH2:59]1>>[C:62]([CH2:61][CH2:60][CH2:59][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([N:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:18])[CH2:15][CH2:16]1)=[O:10])([OH:64])=[O:63]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1
Agent: Br
Agent: O=C(N1CCNCC1)N1c2ccccc2C=Cc2ccccc21
Product: O=C(O)CCCC(=O)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
These materials were prepared using the procedures outlined in steps 2 and 3 of Example 2, except starting with 5-[4-(benzyloxycarbonyl)piperazinocarbonyl]-5H-dibenzo[b,f]azepine in place of the N-[3-(benzyloxycarbonylamino)propyl]carbamazepine in step 2, and thus the product 5-(Piperazinocarbonyl)-5H-dibenzo-[b,f]azepine Hydrobromide in place of the product of step 2, and glutaric anhydride in place of succinic anhydride in the procedures of step 3. The residue (2B) was crystallized from ethyl acetate (10 mL) and petroleum ether (2 mL), placed in a freezer, and filtered to give the acid.
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28])#[CH:21]>>[F:19][C:18]1[C:2]([C:21]#[C:20][C:22]2([OH:29])[CH2:26][CH2:25][N:24]([CH3:27])[C:23]2=[O:28])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: C#CC1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Product: CN1CCC(O)(C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)C1=O
Yield: 30 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one (WO2009/158011A 1) to give the titled compound (34.8 mg, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:12][CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:5])[CH3:2].[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[N:12]([CH2:13][CH2:14][C:15]([CH3:17])([CH3:16])[CH3:18])[C:35](=[O:36])[CH2:34][C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:32])(=[O:33])[N:30]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1NCCC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3,3-dimethylbutylamino)-cyclohexanecarboxylic acid ethyl ester (60.0 mg, 0.243 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 162.0 mg, 0.486 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.49 mL, 0.49 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclohexanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C25H38N4O7S2 570.22, found 571.4 [M+H+].
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH3:41][NH:42][CH3:43]>O1CCOCC1.C(Cl)(Cl)Cl>[CH3:41][N:42]([CH3:43])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Reactant: CNC
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN(C)C)C(=O)c1cc2c(cc1-3)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.061 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (10 mL), and dimethylamine (0.023 mL, 0.408 mmol) was added dropwise. The mixture was stirred at reflux for 52 h. The mixture was diluted to a volume of 250 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting first with a gradient of 0.5% MeOH in CHCl3, and then with 1% MeOH in CHCl3, to yield the product 23 as a solid (0.009 g, 47%): mp 176-178° C. (dec). IR (film) 2922, 1698, 1650, 1483, 1306, 1032, 786 cm−1: 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.63 (s, 1H), 7.43 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H), 4.54-4.48 (t, 8.4 Hz, 2H), 4.29-4.25 (t, J=6.3 Hz, 2H), 3.95 (s, 3H), 3.78-3.74 (t, J=4.8 Hz, 2H), 2.57-2.53 (m, 14H), 2.27 (s, 2H), 2.03-2.02 (m, 2H); ESIMS m/550 (MH+); HRESIMS m/z 550.2558 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 97.57% (C-18 reverse phase. MeOH—H2O, 85:15).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[C:23](=[O:25])[CH3:24]>CN(C=O)C>[CH2:7]([O:22][C:20]1[CH:19]=[CH:18][C:17]([C:23](=[O:25])[CH3:24])=[C:16]([OH:15])[CH:21]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reaction time: 5 h

Procedure:
Potassium carbonate (54 g, 0.39 mol) followed by benzyl bromide (13.9 mL, 0.12 mol) were added to a solution of 2′,4′-dihydroxyacetophenone (20 g, 0.13 mol) in DMF (180 mL). The mixture was stirred for 5 hours and then partitioned between H2O and EtOAc. The organic layer was washed with satd NaHCO3, 1 N HCl, brine, dried over Na2SO4 and concentrated to a clear oil (23.7 g, 81%). 1H NMR (400 MHz, CDCl3): δ 2.56 (s, 3H), 5.02 (s, 2H), 6.51 (m, 2H), 7.33-7.43 (m, 5H), 7.64 (d, J=8.3 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4]/[N:5]=[C:6](/[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH2:21])\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:3](=[O:2])[CH2:4][N:5]=1
Reactant: COC(=O)C/N=C(/c1cc(F)ccc1N)c1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CN=C(c2ccccc2Br)c2cc(F)ccc2N1
Yield: 83.7 %

Procedure:
A solution of 72.7 g (0.199 moles) of (Z)-N-[(2-amino-5-fluorophenyl)(2-bromophenyl)methylene]glycine methyl ester), 1450 mL of toluene, and 42.8 g (0.225 moles) of p-toluenesulfonic acid monohydrate was heated to reflux for 3 hours under nitrogen After cooling, the product crystallized out of the reaction mixture The resultant suspension was filtered and the collected solid was washed twice with 100 mL of toluene, followed by two washes with 100 mL of hexane. The solid was partitioned between 1.0 L of methylene chloride and 1.0 L of saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with 250 mL of methylene chloride. The combined organic layers were washed twice with 250 mL of 1:1 mixture brine/water, dried with Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in 800 mL of methylene chloride and concentrated to give 55.5 g of 5-(2-bromophenyl)-7-fluoro-1,3-dihydro-1,4-benzodiazepine-2 (2H)-one as a light yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:9][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(S)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cccc(Sc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A solution of 3-(methylthio)benzenethiol (19.9 g, 127.3 mmol), prepared as indicated in Rumpf, P., Bull. soc. chim. (1940), 7, pp. 632-4, in acetonitrile (60 mL) was treated with 4-fluorobenzaldehyde (13.4 mL, 127 mmol) followed by potassium carbonate (19.4 g, 140 mmol). After stirring at ambient temperature for 18 hours the suspension was diluted with water (200 mL) and extracted with ethyl acetate (3-fold 300 mL). The combined organic extracts were washed with brine (2-fold 100 mL) and dried (magnesium sulphate) and the solvent removed in vacuo to give a colourless oil. The crude oil was purified by flash column chromatography on silica gel eluting with heptane:ethyl acetate (1:0 changing to 9:1, by volume) to give the title compound as a colourless oil, 33% yield, 10.8 g.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][NH2:22])=O)=[CH:17][N:16]=1.Cl.[C:26](N)(=[NH:28])[CH3:27]>CN(C=O)C.C(OC(=O)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[NH:28][C:26]([CH3:27])=[N:22][N:21]=2)=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Reactant: CC(=N)N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)[nH]1
Temperature: 120 °C
Yield: 20.2 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid hydrazide (300 mg, 0.6 mmol) and acetamidine hydrochloride (87 mg, 0.9 mmol) in DMF (6 mL) was heated at 120° C. for 2 h. A second portion of acetamidine hydrochloride (174 mg, 1.8 mmol) was added. After 8 h the mixture was cooled to room temperature and diluted with ethylacetate (40 mL). The mixture was filtered and the filtrates collected and washed with water (3×10 mL) and brine (10 mL) then dried over sodium sulfate, filtered and concentrated. Purification by chromatography (SiO2, 0-5% dichloromethane:methanol=100:0 to 95:5) followed by purification by HPLC (acetonitrile:water=2:8) gave the title compound (42 mg, 20%) as a white solid. MS: m/e=348.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C=O>[CH3:16][C:15]1[C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cccn2cc(-c3ccc(N)cc3)nc12
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of the product of Example 27 Step B (195 mg) in N,N-dimethylformamide (2 mL) was added triethylamine (0.12 mL) and the mixture cooled to 0° C. 3-chloropropanesulfonyl chloride (0.11 mL) was added dropwise and the mixture stirred for 1.5 hours before the addition of H20 (2 mL). The reaction mixture was partitioned between H2O (15 mL) and ethyl acetate (15 mL). The aqueous layer was brought to pH=9-10 with saturated sodium bicarbonate solution and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, decanted, and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (210 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])([O-])=O.[K+].[K+].F[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]#[N:27])=[CH:18][CH:17]=1>CS(C)=O>[C:26]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])=[CH:17][CH:18]=1)#[N:27]
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 80 °C
Reaction time: 89 h
Yield: 76 %

Procedure:
To a suspension of D-allo-threonine (2.09 g, 17.53 mmol) and K2CO3 (4.04 g, 29.21 mmol) in DMSO (40 mL) was added 4-fluoro-1-naphthonitrile (CAS 13916-99-9, 2.50 g, 14.61 mmol) at room temperature. The reaction mixture was heated to 80° C. and stirred for 89 h. The reaction mixture was allowed to cool to room temperature, quenched with H2O (150 mL) and extracted with EtOAc (3×100 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a light brown solid (3.0 g, 76%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 8.46 (d, J=8.8 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.74 (t, J=7.0 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 4.29-4.20 (m, 1H), 4.08-3.99 (m, 1H), 1.28 (d, J=6.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)O1>>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2
Reactant: Fc1cccc(Cl)c1Br
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Product: Fc1cccc(Cl)c1-c1ccc2[nH]ccc2c1
Yield: 62.7 %

Procedure:
This title compound was prepared analogously to compound 25b using 2-bromo-1-chloro-3-fluorobenzene (39.5 g, 0.19 mol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (37.0 g, 0.15 mol). The title compound (23.1 g, 62%) was obtained. MS (ESI, m/z): 246.0 (M+1).
Reaction SMILES: [C:1](=[O:20])([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:2][CH:3](Cl)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([NH:24][C:25]1[C:26]([I:41])=[C:27]([N:36]([C:38](=[O:40])[CH3:39])[CH3:37])[C:28]([I:35])=[C:29]([C:32]([O-:34])=[O:33])[C:30]=1[I:31])(=[O:23])[CH3:22].[K+].[I-].[Na+]>CN(C=O)C>[C:21]([NH:24][C:25]1[C:26]([I:41])=[C:27]([N:36]([C:38](=[O:40])[CH3:39])[CH3:37])[C:28]([I:35])=[C:29]([C:32]([O:34][CH:3]([O:2][C:1]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:33])[C:30]=1[I:31])(=[O:23])[CH3:22]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(Oc1ccccc1)OC(Cl)CCc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(CCc2ccccc2)OC(=O)Oc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-Chloro-3-phenylpropyl phenyl carbonate (0.30 g, 1.03 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methyl-amino)-2,4,6-triiodobenzenecarboxylate (0.62 g, 0.93 mmol) and sodium iodide (0.014 g, 0.093 mmol) in dry DMF (5 ml). After stirring at 50° C. for 5 hours and at room temperature for 2 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (15 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 0.26 g. Purity by HPLC: 94.4% 1H-NMR (DMSO-d6): delta=1.68 (NCH3COCH3); 2.06 (NHCOCH3); 2.38 (CH2CH); 2.83 (CH2CH2CH); 2.98 (NCH3); 7.02 (CH); 7.19-7.52 (phenyl); 10.15 ppm (NH). FAB/MS: 883 ((M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(N2CCCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 114 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1.0 g, 5.85 mmol) in 15 mL of DMSO was added 1-methylhexahydro-1H-1,4-diazepine (0.8 mL, 6.42 mmol) and potassium carbonate (2.4 g, 17.4 mmol). The reaction mixture was heated at 80° C. for 16 h at which time the reaction was diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water and a saturated sodium chloride solution, dried over Na2SO4 and filtered. Solvents were removed under reduced pressure to give 1-methyl-4-[3-(methyloxy)-4-nitrophenyl]hexahydro-1H-1,4-diazepine (1.77 g, 6.67 mmol) as a yellow solid containing residual DMSO. ESIMS (M+H)+=266
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[N:4]=1)[NH2:2].C(O[CH:24]=[C:25]([C:31](=O)[C:32]([F:35])([F:34])[F:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[C:5]1[N:4]=[C:3]([N:1]2[C:31]([C:32]([F:33])([F:34])[F:35])=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:24]=[N:2]2)[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Reactant: COc1ccc(C)cc1-c1cc([N+](=O)[O-])cc(NN)n1
Product: CCOC(=O)c1cnn(-c2cc([N+](=O)[O-])cc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F

Procedure:
Reaction of the title compound from Example 19 Step C with ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate, according to chemistry described in Example 1 Step A, provided the title compound: LCMS m/z 451.6 [M+H]+.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.NN.[OH-].[Na+]>C(O)C>[NH2:3][CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of the product of Example 3F (28.44 g, 78.9 mmol) in ethanol (400 mL) was treated with hydrazine hydrate (25 mL, 789 mmol), stirred at 70° C. for 2 hours, cooled to 25° C. The solid precipitate was dissolved by addition of aqueous NaOH solution (200 mL, 1 N). The reaction was partitioned between dichloromethane and water. The aqueous was extracted three times with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and concentrated to give the title compound (15.4 g, 85% yield), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][N:15]1CCOCC1.ClC(OCC(C)C)=O.CN.C(O)C>C1COCC1>[CH3:14][NH:15][C:11](=[O:13])[CH2:10][O:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)CONC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
A solution of 2-(tert-butoxycarbonylaminooxy)acetic acid (87a, 1 g, 5.23 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (863 μL, 7.85 mmol) and isobutyl chloroformate (746 μL, 5.75 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of methanamine in ethanol (1.3 mL, 10.46 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo to yield tert-butyl 2-(methylamino)-2-oxoethoxycarbamate (87b, 775 mg, 3.80 mmol).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.C(OCC)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(Cl)Cl
Reactant: Cc1ccc(S)cc1
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(Sc1ccc(C)cc1)Sc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (3.54 g) is dissolved in methanol (140 cc) and a solution of 4-methylthiophenol (21.8 g) in methanol (25 cc) is added. The mixture is stirred for 1 hour at 20° C. and a solution of ethyl dichloroacetate (12.5 g) in methanol (30 cc) is then added. The mixture is allowed to cool, the white precipitate obtained is filtered off, and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil obtained is taken up in diethyl ether (250 cc) and washed four times with N sodium hydroxide solution (50 cc each time) and four times with distilled water (50 cc each time). The ethereal phase is dried over anhydrous sodium sulphate, filtered, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylthiophenoxy)acetate (18 g) is thus obtained as a yellow oil.