Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[C:14]([CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[C:4](=[O:36])[CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.CN(C)C=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].[CH2:48](Br)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O>[CH2:48]([N:23]([C:20]1[CH:21]=[CH:22][C:17]([N:5]2[C:4](=[O:36])[CH2:3][C:42](=[O:45])[N:8]([CH2:2][C:6]3[CH:16]=[CH:15][CH:14]=[CH:9][CH:7]=3)[C:7]3[C:9]4[C:14]([CH:15]=[CH:16][C:6]2=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:18][CH:19]=1)[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.[CH2:48]([N:23]([C:20]1[CH:21]=[CH:22][C:17]([N:5]2[C:4](=[O:36])[CH2:3][C:2](=[O:1])[NH:8][C:7]3[C:9]4[C:14]([CH:15]=[CH:16][C:6]2=3)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:18][CH:19]=1)[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])(=[O:26])=[O:25])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(=O)N(c2ccc(N(Cc3ccccc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(N(Cc3ccccc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3ccccc3c2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %
Yield: 41 %

Procedure:
N-[4-(2,4-Dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide (110 mg, 0.22 mmol) obtained in Example 145, dimethylformamide (1 mL), potassium carbonate (91 mg, 0.66 mmol), and benzyl bromide (31 μL, 0.26 mmol) were mixed, and the mixture was stirred at room temperature for 2 hours and 30 minutes. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 3/2) to give N-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide (47 mg, yield 31%) as white amorphous, and N-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide (54 mg, yield 41%) as white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3ccc(Cl)cc3)nc2c1
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccc(F)cc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as yellow foam. MS: m/e=497.1 [M+H+].
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:21][C:22]2[O:26][C:25]([C:27]([O:29]CC)=[O:28])=[CH:24][CH:23]=2)[NH:7][C:8]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)C.C1COCC1.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:21][C:22]2[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=2)[NH:7][C:8]=1[NH:9][C:10](=[O:20])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:16]=1)(=[O:3])[NH2:2]
Reactant: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)OCC)o3)nc2C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)O)o3)nc2C(N)=O)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.8 g (4.24 mM) of ethyl 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylate are added to 10 ml of an ethanol/THF mixture (50-50). 4 ml of aqueous 3N sodium hydroxide solution are then added and the reaction medium is maintained at 40° C. with stirring for 2 hours. The reaction medium is allowed to cool and is acidified with acetic acid; a solid crystallizes. The solid is filtered off and washed with demineralized water to give, after drying, 1.7 g of 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[O:12])#[N:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][SH:18])[CH3:14].C(N(CC)CC)C>C(OCC)C>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([S:18][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:10][CH:11]=[O:12])#[N:2]
Reactant: N#CCCCCCCC=CC=O
Reactant: CCOC(CS)OCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(CSC(=CC=O)CCCCCCC#N)OCC
Reaction time: 48 h

Procedure:
The starting material is prepared as follows: The mixture of 1.8 g of 9-cyano-2-nonenal, 1.4 g of 2,2-diethoxy-ethanethiol and 50 μl of triethylamine is allowed to stand at room temperature for 48 hours. It is taken up in 100 ml of diethyl ether, the solution washed with water, dried and evaporated, to yield the 9-cyano-3-(2,2-diethoxy-ethylmercapto)-nonenal, showing in NMR spectrum peaks at 9.78, 4.55, 3.57 and 2.61 ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C@H:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.N#N.[C:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])#[CH:31]>C1(C)C=CC=CC=1.[Cu](I)I.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>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C@@H:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:31]#[C:30][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:3]=1)[CH3:11]
Reactant: C[C@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[C@H](Oc1cc(C#C[Si](C)(C)C)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
The compound (S)-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (12.58 g, 33.11 mmol) was dispersed in toluene (100 mL), and triethylamine (14.05 g, 139.06 mmol) and copper iodide (126 mg, 0.66 mmol) were added successively. Under the protection of N2 atmosphere, PdCl2(PPh3)2 (465 mg, 0.66 mmol) was added. The reaction mixture was heated to 30° C., stirred for 0.5 h. Ethynyltrimethylsilane (9.11 g, 92.71 mmol) was added dropwise, gradually warmed to 90° C., and stirred overnight. Through HPLC test, it was found that the raw materials were completely reacted. The reaction liquid was cooled down, washed with water, and the toluene layers were combined. The toluene layer was dried over anhydrous Na2SO4, concentrated; the residue was purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as yellow solid (10.6 g, yield: 80%).
Reaction SMILES: OCC1C2SC(S)=NC=2C=CC=1.[F:13][C:14]([S:17]([O-:20])(=[O:19])=[O:18])([F:16])[F:15].[C:21]([CH2:24][N+:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2)(=[O:23])N>>[F:13][C:14]([S:17]([O-:20])(=[O:19])=[O:18])([F:16])[F:15].[OH:23][CH2:21][CH2:24][N+:25]12[CH2:32][CH2:31][N:28]([CH2:27][CH2:26]1)[CH2:29][CH2:30]2
Reactant: NC(=O)C[N+]12CCN(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OCc1cccc2nc(S)sc12
Product: OCC[N+]12CCN(CC1)CC2

Procedure:
Starting with the product of Example 5, Step 2 and following the procedure of Example 4, Step 3, but substituting 1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2 ]octane trifluoromethylsulfonate, with 1-(2-hydroxyethyl)-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethylsulfonate one obtains the desired product.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CC([O-])(C)C.[K+].CC(O)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]Cl)([O-:31])=[O:30].Cl>O>[F:1][C:2]1[C:3]([NH:17][S:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N+:29]([O-:31])=[O:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1SCl
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccccc1SNc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 1 h
Yield: 25.6 %

Procedure:
To a solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.05 g, 0.2 mmol) and a 1.0 M solution of t-BuOK in t-BuOH (1.0 mL, 1.0 mmol) was added nitrobenzene-sulfenyl chloride (0.044 g, 0.23 mmol) in one portion, and the resulting brown solution was stirred for 60 min. The reaction was diluted with water (2 mL) and neutralized to pH 7 with 1N HCl. The aq. phase was extracted with EtOAc (5 mL), and the organics were combined, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase chromatography to yield the title compound (0.020 g, 26%) as a yellow solid: mp 184° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=7.25 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.59 (m, 1H), 7.36 (m 2H), 7.29 (m, 2H), 6.88 (m, 2H), 6.23 (bs, 1H), 5.19 (s, 2H); HPLC-MS (ESI) m/z 391 (M+H)+, 389 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>CN(C=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-methylnicotinic acid (5.00 g, 36.5 mmol) in DMF (150 mL), 1-hydroxybenzotriazole (4.92 g, 36.5 mmol), N-ethyl-N-(3-dimethylaminopropyl) carbodiimide hydrochloride (8.38 g, 45.7 mmol) and 4-methylmorpholine (16.0 mL, 145.8 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 30 minutes after which N,O-dimethylhydroxylamine hydrochloride was added (3.55 g, 36.5 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and 0.2 N NaHCO3. The phases were separated and the aqueous phase was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 1.11 g of the desired product (yield: 29%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([O:18]C)([O:16]C)=[O:15])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.CCOCC>Br.C(O)(=O)C>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@H:8]([NH:12][CH2:13][P:14]([OH:18])([OH:16])=[O:15])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: COP(=O)(CN[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(O)O
Reaction time: 2 h

Procedure:
(S)-3-(Biphenyl-4-yl)-2-(dimethylphosphonomethyl-amino)-propionic acid (278 mg, 0.76 mmol) is dissolved in a 30% solution of hydrobromic acid in acetic acid (10 mL) under nitrogen. After 2 hours, ether (50 mL) is added and the product precipitates. The mixture is kept at 0° for 18 hours and then filtered. The solid is dissolved in 0.1N sodium hydroxide (25 mL) and the insoluble material is filtered. The filtrate is acidified with 2N hydrochloric acid (5 mL). The gelatinous solid is filtered, washed with water and dried under high vacuum at 75° to give the (S)-3-(biphenyl-4-yl)-2-(phosphonomethylamino)-propionic acid as a white powder; m.p.: 241° (dec.); [α]D =+33.16 (c 0.95, 0.1N NaOH). ##STR30##
Reaction SMILES: [NH:1]([C:3](=[O:25])[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)=[O:5])[NH2:2].[N+](C1C=CC(O[C@H]2CC[C@H](C(OCC)=O)CC2)=CC=1)([O-])=O>>[NH:1]([C:3](=[O:25])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)=[CH:23][CH:24]=1)=[O:5])[NH2:2]
Reactant: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCOC(=O)[C@H]1CC[C@H](Oc2ccc([N+](=O)[O-])cc2)CC1
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)C(=O)NN)cc2)CC1

Procedure:
Intermediate 3 was synthesised using the reaction conditions described for Intermediate 1, starting from Intermediate 2, described in the reaction conditions for Intermediate 1(i).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[SH-].[Na+].[N+](C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1)([O-])=O.O>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 98.5 %

Procedure:
A 1-nitroanthraquinone (98.0% purity) and water mixture with slurry concentration of 17.2% and a 12.0% aqueous solution of sodium hydrosulfide were added dropwise into a 2,000-volume-part glass-made vessel under agitation while maintaining the internal temperature of the vessel at 94°-96° C. The feeding rates of the 1-nitroanthraquinone-water mixture and the 12.0% sodium hydrosulfide solution were maintained constant at 1,055 part/hr and 945 part/hr, respectively. One hour after start of pouring, withdrawal of the reaction mixture from the bottom of the flask was started, with the efflux rate being maintained constant at 2,000 part/hr. The flow rate of 1-aminoanthraquinone (98.5% purity) in the effluent obtained from the 6th hour and afterward was 158 part/hr.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36]([O:39][CH2:40][Br:41])(=[O:38])[CH3:37]>C(#N)C>[Br-:41].[C:36]([O:39][CH2:40][N:33]1[CH2:34][NH+:30]([CH2:29][C@@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:35])[C@H:10]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH:27]=[CH:26][N:25]=[N:24]4)=[CH:21][CH:22]=3)[C:13]2=[O:28])[CH3:11])[N:31]=[CH:32]1)(=[O:38])[CH3:37]
Reactant: C[C@@H](N1CCN(c2ccc(-n3ccnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)OCBr
Solvent: CC#N
Product: CC(=O)OCN1C=N[NH+](C[C@](O)(c2ccc(F)cc2F)[C@@H](C)N2CCN(c3ccc(-n4ccnn4)cc3)C2=O)C1
Product: [Br-]
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added bromomethyl acetate (0.1 ml), and the mixture was stirred for 24 hours at 50° C. The reaction mixture was purified by silica gel flush chromatography (silica gel 25 g, eluent: ethyl acetate→acetone→acetone/ethanol=10/1). The residue purified was crystallized from ethanol to give 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium bromide (Compound 10, 0.135 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([NH2:10])=[S:9])=[CH:5][C:4]([CH3:11])=[N:3]1.[CH3:12][I:13]>>[IH:13].[CH3:1][N:2]1[C:6]([NH:7][C:8](=[NH:10])[S:9][CH3:12])=[CH:5][C:4]([CH3:11])=[N:3]1
Reactant: CI
Reactant: Cc1cc(NC(N)=S)n(C)n1
Product: CSC(=N)Nc1cc(C)nn1C
Product: I

Procedure:
(1,3-Dimethyl-5-pyrazolyl) thiourea (17.0 g) and 14.2 g methyl iodide were reacted as described in Example V to give 18.0 g. of the product, mp 158°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].O.[C:24]([OH:28])(=[O:27])[CH:25]=O>C(#N)C.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:25]([C:15]2[CH:16]=[CH:17][C:18]([F:19])=[C:13]([O:12][CH3:11])[CH:14]=2)[C:24]([OH:28])=[O:27])[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: COc1cc(B(O)O)ccc1F
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1F
Temperature: 55 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A mixture of 3-aminobenzamide (136 mg, 1.0 mmol), 7C (170 mg, 1.0 mmol) and glyoxylic acid monohydrate (92 mg, 1.0 mmol) in acetonitrile (5.0 mL) and DMF (1.2 mL) was heated at 55° C. for 2.0 h and then stirred at rt for 18 h. After removal of solvent, the crude was purified by silica gel column chromatography eluting with gradient methanol in methylene chloride to give 7D as a solid (190 mg, 60% yield). 1H NMR (400 MHz, Methanol-d4) δ ppm 3.85 (s, 3H) 5.11 (s, 1H) 6.79 (d, J=7.03 Hz, 1H) 7.04-7.15 (m, 5H) 7.27 (dd, J=8.35, 1.76 Hz, 1H); LC-MS 319 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(N(CC)CC)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:28]=[CH:27][C:26]([F:29])=[CH:25][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:19][C:18]=3[F:24])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: O=C(NCc1ccc(O)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(OCc2ccccn2)cc1F)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 100 mg (0.25 mmol.) 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-N-(2-fluoro-4-hydroxy-benzyl)-nicotinamide [Prepared analogous to preparation 35 by substituting 2-chloro-5-fluoro-nicotinic acid (EP 0634413 A1)], 10 mL DMF and 175 mg (1.25 mmol.) potassium carbonate was added a solution of DMF (5 mL) containing 82 mg (0.5 mmol.) 2-chloromethyl-pyridine hydrochloride (Aldrich) and 1 equivalent of triethyl amine. The resulting mixture was stirred for 3 days at room temperature. Reaction mixture was poured into ice water (200 mL) and the resulting solid was filtered, washed with cold water and dried in vacuo to afford desired product.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: OCc1cccnc1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
NaH (0.19 g, 4.80 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (5 mL), the suspension cooled to 0° C. and 3-pyridylcarbinol (0.40 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (1.33 g, 4.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 3-pyridylcarbinol in THF were added after 7 and 25 h, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) is followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid) and Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 40% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-3-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (46.3 mg, 3.8%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[F:15][C:16]([F:40])([F:39])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:15][C:16]([F:39])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COc1ccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Prepared analogously to Example 2 b from 1-(4-methoxy-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.CSC1N=C(O)C2CCN([C:37]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:40]=[CH:39][N:38]=3)CCC=2N=1.O=P(Cl)(Cl)Cl.[CH3:54]C#N>CCOC(C)=O>[CH3:24][S:23][C:4]1[N:3]=[C:2]([NH:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([F:44])([F:45])[F:46])=[CH:37][CH:54]=2)[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: CSc1nc(O)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CC#N
Reactant: CSc1nc(Cl)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
4-Chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine. To a solution of 2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (1.8 g, 4.92 mmol) in CH3CN (40 mL) was added POCl3 (1.4 mL, 14.8 mmol). After 15 min at 80° C., the mixture was cooled to rt, diluted with EtOAc, and quenched slowly with satd. aq. NaHCO3. The organic layer was separated, dried (MgSO4), and concentrated. The crude residue was purified (FCC) to give the title compound (1.6 g, 89%).