Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:35](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]5[CH:28]=[CH:27][C:26]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][CH:24]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:46][CH3:47].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:35][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]5[CH:28]=[CH:27][C:26]([N:29]6[CH2:30][CH2:31][O:32][CH2:33][CH2:34]6)=[CH:25][CH:24]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:46][CH3:47]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNc4ccc(N5CCOCC5)cc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNc4ccc(N5CCOCC5)cc4)ccnc3[nH]1)cn2C
Yield: 104.7 %

Procedure:
The product is prepared by following the procedure described in example 34, stage (k), starting with 0.05 g of the [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-ylphenyl)amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34, stage (k) and 0.4 cm3 of 5N potassium hydroxide. 0.04 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(4-morpholin-4-ylphenyl)amine is obtained with the following characteristics:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.Cl.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44]Cl>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][O:38][CH3:39])=[CH:32][CH:31]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:44][CH2:43][N:42]([CH3:46])[CH3:41])[C:13]=2[S:21]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)(=[O:22])=[O:23])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCCCC3)[nH]c3ccccc23)cc1
Reactant: CN(C)CCCl
Agent: Cl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCCCC3)n(CCN(C)C)c3ccccc23)cc1
Yield: 73.7 %

Procedure:
Substantially the same procedure as in Example 243 was repeated using Compound 244 (1.32 g, 2.40 mmol) obtained in Example 245 and 2-dimethylaminoethylchloride hydrochloride (345 mg, 2.40 mmol) to give 1.1 g (yield: 74%) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.S(Cl)(Cl)=O.[OH:17][CH2:18][CH2:19][NH2:20]>C(Cl)(Cl)Cl>[OH:17][CH2:18][CH2:19][NH:20][C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: O=C(NCCO)c1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 1H-benzo[d]imidazole-2-carboxylic acid (1.50 g, 9.26 mmol) and thionyl chloride (10 mL). After heating at reflux for 16 h, the suspension was cooled to room temperature and filtered. The filter cake was washed with toluene (10 mL) and dried under vacuum at room temperature for 5 h. The resulting solid was charged into a 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, followed by chloroform (10 mL) and 2-hydroxyethylamine (559 mg, 9.17 mmol). After stirring at reflux for 16 h, the reaction mixture was concentrated under reduced pressure, and the resulting residue was triturated with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 73% yield (1.41 g) of 152a as a white solid: mp 194-195° C.; 1H NMR (500 MHz, DMSO-d6) d 13.13 (s, 1H), 8.74 (s, 1H), 7.71-7.29 (m, 4H), 4.80 (s, 1H), 3.55 (dd, 2H, J=10.5, 5.5 Hz), 3.38 (dd, 2H, J=10.5, 5.5 Hz); MS (APCI+) m/z 206.6 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[CH:25]1([CH2:30][C@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:32](=[O:33])[C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 86 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (128 mg, 77%) as a white foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C25H37N3O2SiCl2 (M+H)+ 510.2105, observed 510.2105; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.81 (m, 1H, ArCHCO), 3.84 (t, J=5.4 Hz, 2H, OCH2), 4.04 (t, J=5.4 Hz, 2 H, NCH2), 6.40 (d, J=2.3 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.58 (d, Jo=8.3 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.68 (s, 1H, NH).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6]OS(O)(=O)=O.C([O:14][C:15]([C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][C:22]([Br:29])=[C:23]([F:28])[CH:24]=2)[N:19]([CH:30]2[CH2:32][CH2:31]2)[C:18]=1[SH:33])=O)C.Cl>C1COCC1>[Br:29][C:22]1[CH:21]=[C:20]2[C:25]([C:26](=[O:27])[C:17]3[C:15](=[O:14])[NH:6][S:33][C:18]=3[N:19]2[CH:30]2[CH2:32][CH2:31]2)=[CH:24][C:23]=1[F:28]
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: NOS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]sc2c1c(=O)c1cc(F)c(Br)cc1n2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of NaHCO3 solution (51 mg, 0.9 ml water) and hydroxylamine-O-sulfonic acid (27 mg, 0.24 mmole, 4.2 equiv.) is added to a stirred solution of 7-Bromo-1-cyclopropyl-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6, 22 mg, 0.057 mmole) in THF (0.7 ml). The reaction mixture is stirred at room temperature for approximately 3 hours until the reaction is complete. The reaction mixture is acidified by the addition of 0.5N HCl and filtered. The resulting solid is washed with water (3×) and dried yielding 7 as a white solid. 1H NMR (DMSO-d6) δ: 8.39 (d, 1H), 8.06 (d, 1H), 3.63 (m, 1H), 1.41 (m, 2H), 1.26 (m, 2H). 19F NMR (DMSO-d6) δ: 114.9 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.C1CCCCC1.[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step A) (4.0 g, 16 mmol) in tetrahydrofuran (25 mL) was cooled to −78° C., and then treated dropwise with 2 M n-butyllithium in cyclohexane (8.6 mL, 17.2 mmol). The reaction mixture was stirred for a further 30 minutes, and then a solution of hexachloroethane (4.2 g, 18 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction mixture was stirred for 1 h, warmed to room temperature, and quenched with water (50 mL). The resulting solution was extracted with dichloromethane, dried (MgSO4), and concentrated under reduced pressure to give 4.38 g of title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]2[CH2:17][N:16]([C:18]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:19])[CH2:15][CH:14]([C:26]([OH:28])=O)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O[N:30]=[C:31]([O:33][CH2:34][CH3:35])[NH2:32]>>[CH2:34]([O:33][C:31]1[N:32]=[C:26]([CH:14]2[CH2:13][CH:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([F:1])[CH:3]=3)[CH2:17][N:16]([C:18]([N:20]3[CH2:21][CH2:22][S:23][CH2:24][CH2:25]3)=[O:19])[CH2:15]2)[O:28][N:30]=1)[CH3:35]
Reactant: CCOC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Product: CCOc1noc(C2CC(c3ccc(C(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 4, 151 mg (0.280 mmol) of the compound from Example 85A and 43 mg (0.420 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 38 mg (25% of theory).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 21 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 21% of theory, C34H41N7O5 (627.8) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU77##
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH3:25])=[O:12])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].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>[CH2:24]([O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[C:11]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1)=[O:12])[CH3:25]
Reactant: CCOc1ccc2ccccc2c1C(=O)n1cc(Br)c2cccnc21
Reactant: CS(=O)(=O)c1ccc(B(O)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: C1CCOC1
Product: CCOc1ccc2ccccc2c1C(=O)n1cc(-c2ccc(S(C)(=O)=O)cc2)c2cccnc21
Temperature: 60 °C

Procedure:
(3-Bromo-pyrrolo[2,3-b]pyridin-1-yl)-(2-ethoxy-naphthalen-1-yl)-methanone 85 (35 mg, 0.0088 mmol), 4-Methanesulfonyl-phenylboronic acid (35 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg) were stirred in tetrahydrofuran (16 mL) and potassium carbonate solution (8.0 mL, 1 M aqueous). The reaction mixture was stirred over night at 60° C. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and brine. The organic portion was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by flash chromatography (ethyl acetate:hexanes 20%-100%). The desired product, 84 was obtained as a pale yellow powder (10 mg, 20%).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]1([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][CH:17]=2)=[N:1]1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Reaction time: 48 h
Yield: 90 %

Procedure:
To a stirred and cooled (0° C.) mixture of 4.5 parts of 2-amino-2-methyl-1-propanol and 130 parts of dichloromethane were added portionwise 4.93 parts of 4-(phenylmethoxy)benzoyl chloride. Upon complete addition, stirring was continued for 48 hours at room temperature. The precipitate was filtered off and the filtrate was evaporated. The residue was stirred in 2,2'-oxybispropane. The precipitated product was filtered off and stirred in 9.6 parts of thionyl chloride during 1 hour. After evaporation, the residue was taken up in a sodium hydroxide solution 10%, crushed ice and methylbenzene. The separated organic layer was washed with water, dried, filtered and evaporated, yielding 5 parts (90%) of 4,5-dihydro-4,4-dimethyl-2-[4-(phenylmethoxy)phenyl]oxazole as a residue (int. 1).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.Cl[CH2:41][C:42]([N:44]([CH3:46])[CH3:45])=O>>[CH3:45][N:44]([CH3:46])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C)C(=O)CCl
Product: COc1cc(NCCCc2ccc(OCCN(C)C)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 69.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-dimethylacetamide (6.6 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.3 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH:11]([N:14]=[N:15][C:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12].O>CO>[CH:11]([N:14]=[N:15][C:16]1([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(S(=O)(=O)c2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 6.57 grams (.04 moles) of sodium benzenesulfinate in 60 ml of 70% aqueous methanol in a 125 ml erlenmeyer flask was added 6.4 grams (.034 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) dropwise over 25 minutes while holding the temperature at 0° to 5° C with an ice bath. After the addition was complete, the reaction was stirred for 60 minutes at 0° to 5° C, poured into 200 ml cold water and extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml of water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 5.95 grams (59.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-(benzenesulfonyl)-cyclohexane.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:36][O:37][CH2:38][CH3:39])[N:19]([CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=3)[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1>CC#N>[NH2:6][C:7]1[C:16]2[N:17]=[C:18]([CH2:36][O:37][CH2:38][CH3:39])[N:19]([CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]3[CH:26]=[C:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][CH:30]=3)[C:3](=[O:4])[CH2:2][Cl:1])[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCNCc1cccc(CC(=O)OC)c1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (0.059 mL) was added to the product of step (v) (25 mg) in MeCN (2 mL) at rt under nitrogen. The resulting solution was stirred at rt for 2 h, then concentrated in vacuo and azeotroped with toluene, yield 30 mg.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1cccc(/C=C/c2cccnc2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cccnc2)c1
Yield: 25.6 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (1.15 g), 3-[(E)-2-(3-aminophenyl)vinyl]pyridine (1.23 g) and potassium carbonate (1.1 g) in 1,4-dioxane (15 ml) was stirred under reflux for 22 hours. After cooling, insoluble materials were removed by filtration and the filtrate was concentrated. The residue was chromatographed on silica gel column (2% methanol in chloroform) to give 3-nitro-2-[3-[(E)-2-(3-pyridyl)vinyl]phenylamino]pyridine (510 mg) as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14](=O)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC1C=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]2.C1CCN2C(=NCCC2)CC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc2ccncc2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Yield: 86.8 %

Procedure:
3.5 g (14.2 mmol) (S)-3-Acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (266) were dissolved in 95 ml MeOH and treated with 2.34 g (16.9 mmol) potassium carbonate and stirred over night. After evaporation of all volatiles the residue was taken up in 60 ml of degassed DMF, 1.27 g (15 mmol) 6-Fluoro-7-chloroisoquinoline and 2.25 ml (15 mmol) DBU were added. After 3 h at RRT the mixture was concentrated, taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 40% ethyl acetate in heptane) gave 4.5 g of the expected compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: NN1CCOCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (27.8 g, 0.14 mole) in CH2Cl2 (350 mL) at 0° C. was added a solution of 4-aminomorpholine (10.2 g, 0.1 mole) and triethylamine (10.2 g, 0.1 mole) in CH2Cl2 (40 mL) via addition funnel over 1 h. A white ppt formed during the addition. After the addition was complete, the ice bath was removed and the reaction was stirred an additional 1 h. The solid was collected by filtration, re-suspended in Et2O and filtered to give the desired product as a white solid (15 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].CO>ClCCl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: CC1(c2ccc(Cl)cc2)OCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 55.4 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), ethylene glycol (1.7 mL, 30 mmol) and dry methanol (1.2 mL) in dry dichloromethane (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxolane (21) as a colourless oil (1.1 g, 51%). 1H nmr (300 MHz, CDCl3) 1.63 (s, 3H, CH3), 3.72-3.82 (m, 2H, OCH2), 3.98-4.09 (m, 2H, OCH2), 7.42 (d, J=8.6 Hz, 2H, 2×ArH), 7.30 (d, J=8.6 Hz, 2H, 2×ArH).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]([CH3:18])[C:14]([O:16]C)=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:14](=[O:16])[CH:13]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[CH3:18]
Reactant: NCCN
Reactant: COC(=O)C(C)c1cc(C)c(O)c(C(C)(C)C)c1
Product: Cc1cc(C(C)C(=O)NCCN)cc(C(C)(C)C)c1O
Reaction time: 1 h
Yield: 84.9 %

Procedure:
125 g of methyl 3-tert-butyl-4-hydroxy-5-methylphenylpropionate and 300 g of ethylenediamine are heated together at 110° C. for 5 hours, after which a vacuum is applied and the resulting methanol and the excess ethylenediamine are distilled off. 0.3 l of toluene are added to the residue, and the mixture is left to stand at room temperature for one hour. The precipitate is filtered off under suction and dried to give 118 g of the product which, after recrystallization from ethyl acetate, has a melting point of 156°-159° C.