Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[NH4+:10]>O1CCOCC1.O.C(O)(=O)C>[CH:5]1[C:6]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[O:7][C:1]=2[CH:2]=[CH:3][C:4]=1[NH2:10]
Reactant: [NH4+]
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C

Procedure:
Following method B, dimethylsulfamoyl chloride (60 mL, 550 mmol) was added to a gently refluxing solution of 4-aminophenol (55 g, 500 mmol) and triethylamine (56 g, 550 mmol) in tetrahydrofuran (350 mL). The reaction mixture was refluxed for 2 h and then cooled to room temperature and then filtered to remove the solids. The filtrate was diluted with ethyl acetate and washed with 2 N HCl and brine, dried (Na2SO4) and concentrated to give crude N′-(4-hydroxy-phenyl)-N,N-dimethyl-sulfamide (108 g). The crude N′-(4-hydroxy-phenyl)-N,N-dimethyl-sulfamide (108 g, 500 mmol) was dissolved in dichloromethane (750 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (130 g, 550 mmol) was added. The reaction mixture was stirred for 35 minutes and then filtered. The solids were washed with dichloromethane and the filtrate was concentrated. The crude material was purified by column chromatography to provide the benzoquinoneimine (85 g). Potassium t-butoxide (0.30 g, 2.5 mmol) was added to a cooled (2° C.) solution of 2-cyclohexanonecarboxylic acid ethyl ester (4.2 mL, 25 mmol) in tetrahydrofuran (60 mL). The reaction mixture was stirred at 2° C. for 10 min and then a solution of benzoquinoneimine (5.4 g, 25 mmol) in tetrahydrofuran (45 mL) was added. After 1 hour, the mixture was quenched with glacial acetic acid (0.14 mL) and stirred at 2° C. for 40 min, and then concentrated. The crude material was dissolved in ethyl acetate and washed with brine, dried (Na2SO4), and concentrated. The material was purified by flash column chromatography (elution with 30% ethyl acetate-hexane) to provide the desired phenolic cyclohexanone (6.8 g). The phenolic cyclohexanone (0.96 g, 2.5 mmol) was dissolved in dioxane (10 mL) and 6 N hydrochloric acid (10 mL) was added and the mixture was heated to reflux for 2.5 hours. The reaction mixture was diluted with water and made basic with concentrated ammonium hydroxide. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. Analytical analysis indicated complete furan formation, but incomplete sulfonyl urea hydrolysis. The crude mixture was dissolved in acetic acid (10 mL) and 6 N HCl (10 mL) was added. The mixture was refluxed for 12 hours. After cooling to room temperature, the reaction mixture was cooled to 0° C. and concentrated ammonium hydroxide was added until basic. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with 20% aqueous ammonium hydroxide and brine, dried (Na2SO4) and concentrated. Column chromatography purification provided 6,7,8,9-tetrahydro-dibenzofuran-2-ylamine (74 mg).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[Si:32]([O:39][C:40]1[CH:41]=[C:42]([Mg]Br)[CH:43]=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].II.[Mg]>C1COCC1.C(Cl)Cl.CO>[Si:32]([O:39][C:40]1[CH:41]=[C:42]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:9])[CH:43]=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc([Mg]Br)c1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Agent: II
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)sc2c1
Yield: 73.1 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.6 g, 3.75 mmol) in THF (15 mL) was treated with a 0.6 M THF solution of 3-(t-butyldimethylsilyloxy)phenylmagnesium bromide (16 mL, 9.60 mmol) (prepared from the product of preparation 3, catalytic iodine, and magnesium turnings in THF) to provide, after chromatography (silica gel, 5-10% MeOH in CH2Cl2) 1.65 g (73%) of the title compound as a yellow oil: 1H NMR d 0.11 (s, 6H), 0.95 (s, 9H), 1.45 (m, 2H), 1.61 (m, 4H), 2.50 (m, 4H), 2.76 (t, J=5.9 Hz, 2H), 3.89 (s, 3H), 4.09 (t, J=5.9 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.90 (s, 1H), 6.96-7.10 (m, 3H), 7.34 (m, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H); MS (FD) m/e 601 (M+); Anal. calc'd. for C35H43NO4SSi: C, 69.85; H, 7.20; N, 2.33. Found: C, 69.83; H, 7.34; N, 2.34.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:31])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:23]1[C:22](=[O:31])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: O=C1NC(c2ccc(F)cc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3ccc(F)cc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Reaction time: 72 h
Yield: 62 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,4-difluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. After 72 h, the unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5i as an off-white solid (78 mg, 62%). Analytical data for 5i: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.1 Hz, 1H), 8.15 (td, J=9.0, 6.4 Hz, 1H), 7.35-7.27 (m, 5H), 7.26-7.23 (m, 1H), 7.11-7.05 (m, 2H), 7.01-6.92 (m, 3H), 6.83 (ddd, J=12.4, 8.4, 2.5 Hz, 1H), 4.09 (d, J=7.1 Hz, 1H), 3.61 (ddd, J=10.1, 6.9, 4.6 Hz, 1H), 3.34 (dd, J=14.9, 4.6 Hz, 1H), 2.42 (dd, J=14.8, 10.1 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 169.0, 162.6 (dd, JCF=252.4, 12.8 Hz), 159.4 (dd, JCF=247.4, 11.2 Hz), 148.8, 137.9, 137.2, 136.7, 129.7 (dd, JCF=9.3, 4.8 Hz), 129.2, 129.0, 128.6, 128.3, 128.0, 126.8, 113.7 (dd, JCF=10.6, 3.5 Hz), 112.8 (dd, JCF=21.7, 3.1 Hz), 110.2 (d, JCF=3.5 Hz), 104.2 (t, JCF=26.3 Hz), 47.3, 38.4, 32.7; IR (film) cm−1 1771, 1632, 1597, 1535, 1494, 1448, 1267, 1138, 1124, 1105, 1090, 909, 850, 732, 697; LRMS (ESI): Mass calcd for [M+H]+ C25H19F2N2O2: 417.1. found 417.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel AD-H; 10% IPA/hexanes 1.0 mL/min, 280 nm), Rt1 (minor)=25.4 Rt2 (major)=30.9 min; er=98:2.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][C@@H:3]1[C:12]([O:14]CC)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[CH2:17]([NH:24][C:12]([C@H:3]1[N:2]([CH3:1])[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4]1)=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)[C@H]1CC[C@@H](C(=O)OCC)N1C
Solvent: Cc1ccccc1C
Product: CCOC(=O)[C@H]1CC[C@@H](C(=O)NCc2ccccc2)N1C

Procedure:
A solution of diethyl cis-1-methylpyrrolidine-2,5-dicarboxylate (10.95 g, 0.0478 mole) and benzylamine (5.2 ml, 0.048 mole) in 30 ml xylene was refluxed 72 hours at 140°C. After evaporation of the xylene in vacuo, the oily residue was fractionated on a Vigreux column. After an initial fraction of the starting compound (0.49 g), the product was collected: 7.11 g (boiling point 160°C, 0.25 mm).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[CH2:18]([Li])[CH2:19][CH2:20][CH3:21].[CH:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[C:21]1([C:8]2[CH:17]=[CH:12][CH:11]=[CH:10][C:9]=2[C:35]2([OH:37])[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=[CH:10][CH:9]=3)([OH:38])[C:27]3[C:36]2=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: [Li]CCCC
Reactant: Brc1ccccc1-c1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccccc2-c2cccc3ccccc23)c2ccccc2C(O)(c2ccccc2-c2cccc3ccccc23)c2ccccc21
Yield: 84.7 %

Procedure:
Under an atmosphere of argon, 1-(2-bromophenyl)naphthalene (5.4 g, 19 mmole, 2.8 eq) was dissolved into a mixed solvent composed of anhydrous toluene (25 ml) and anhydrous THF (25 ml) and the resultant solution was cooled at −40° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 14 ml, 21 mmole, 1.1 eq) was added and the resultant solution was stirred at −20° C. for 1 hour. To the obtained solution, anthraquinone (1.4 g, 6.7 mmole) was added and the resultant mixture was stirred at −20° C. for 1 hour and at the room temperature for 3 hours and left standing for one night. To the obtained reaction mixture, a saturated aqueous solution of ammonium chloride (20 ml) was added. The formed solid was separated by filtration, washed with water, methanol and acetone and a white solid (3.5 g, 85%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[S:6](=[O:14])(=[O:13])[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Br:17][C:16]1[C:2]([NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:3][C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6](=[O:14])(=[O:13])[C:5]=2[CH:15]=1
Reactant: Nc1cc2c(cc1Br)S(=O)(=O)c1ccccc1-2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc2c(cc1Br)S(=O)(=O)c1ccccc1-2

Procedure:
2-Amino-3-bromo-5,5-dioxidodibenzothiophene (DE 2638081; 0.309 g, 1.0 mmol) was suspended in a solution of DCM (5 ml) and triethylamine (0.111 g, 1.1 mmol). Pivaloyl chloride (0.132 g, 1.1 mmol) was added dropwise and the resultant mixture stirred for 5 days at ambient temperature. The mixture was reduced to dryness and the residue was triturated with methanol. NMR: 9.25 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.80 (t, 1H), 7.68 (t, 1H), 1.28 (s, 9H); m/z 394/396.
Reaction SMILES: [CH2:1]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:16][C:17]([OH:19])=[O:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCCCCCc1ccc(C=CC(=O)O)cc1
Temperature: 100 °C

Procedure:
9.4 G. of p-n-hexylbenzaldehyde in 5 ml. of absolute pyridine are treated with 5.15 g. of malonic acid and 5 drops of piperidine. Then, the mixture is heated at 100° C. for 11 hours, and, subsequently, poured on to cold aqueous hydrochloric acid and extracted with ether. The p-n-hexylcinnamic acid obtained after recrystallization of the crude product from hexane/ether has a melting point of 107°-109° C.
Reaction SMILES: O1CCC(N2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)C=N2)CC1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[CH:50]=CC(B3OC(C)(C)C(C)O3)=[CH:47][CH:46]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[CH:46]=[CH:47][C:10]([C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:19]=4)[CH:15]=[N:16][CH:17]=3)=[CH:11][CH:50]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: Nc1cc(-c2cncc(-c3cnn(C4CCOCC4)c3)c2)cc(-c2ccccn2)n1
Reactant: CC1OB(c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cncc(-c4cc(N)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
This compound is prepared analogously to 5″-[1-(Tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-[2,2′;4′,3″]terpyridin-6′-ylamine (Example 2.156) by replacing 1-(tetrahydro-pyran-4-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Intermediate B18) with 4-[4-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([OH:56])[C:15](=[O:55])[N:16]([CH:28]([CH3:54])[CH:29]([C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)[CH2:30][C:31]1[O:32][C:33]([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:34][CH:35]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8](=[C:14]([OH:56])[C:15](=[O:55])[N:16]([CH:28]([CH3:54])[CH:29]([C:45]1[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=1)[CH2:30][C:31]1[O:32][C:33]([C:36](=[O:44])[NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:34][CH:35]=1)[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
40 mg of methyl 3-tert-butoxycarbonyl-4-hydroxy-4-[N-[(1RS,2RS)-1-methyl-2-(4-nitrophenyl)-3-(5-(phenylcarbamoyl)-2-furyl)propyl]-N-(2-naphthylmethyl)carbamoyl]butanoate was dissolved in 5 ml of chloroform, and 68 mg of Dess-Martin reagent was added thereto, followed by stirring at room temperature for one hour. The reaction solution was poured into a mixed solution of a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium thiosulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography (Kieselgel™60F254, Art™5744; hexane/ethyl acetate=3/2) to obtain 16 mg (yield: 40%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH3:52])=[O:50]>C(Cl)Cl>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:49](=[O:50])[O:51][CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a 50 mL round bottom flask charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (380 mg, 0.705 mmol) in DCM (10 ml) was added pyridine (1 ml) followed by methyl chloroformate (65 μl, 0.847 mmol). The flask was capped and the contents stirred at room temperature for 16 h. An additional aliquot of methyl chloroformate (65 μL, 0.847 mmol) was added to push the reaction to completion. The volatiles were removed in vacuo, the resulting residue redissolved in DCM and washed with saturated copper sulfate solution (2×10 mL). The organics were separated using a phase separator cartridge and concentrated. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 80 g prepacked) eluting with ethyl acetate/hexanes to give (R)-methyl (6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (371 mg, 0.622 mmol, 88%) as a white solid. MS ESI calc'd. For C36H33N6O3 [M+H]+ 597. found 597.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C:11]([OH:15])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>O>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
8.55 ml (64.69 mmol) of 4-toluoyl chloride are added dropwise to 10.52 ml (109.96 mmol) of tert-butanol and 10.46 ml (129.37 mmol) of pyridine while cooling in ice. The mixture is stirred at room temperature for 12 hours. After reaction is complete, water is added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and evaporated. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 50:1). 7.76 g (40.36 mmol, 62% yield) of the title compound are obtained as a colourless oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1>C(N(CC)CC)C.CN(C=O)C>[CH3:5][O:4][C:2]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[NH:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][CH:10]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C=NN)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(C=NNC(=O)OC)cc1
Reaction time: 168 h

Procedure:
1.74 g (22.7 mmol) of methyl chloroformate are added dropwise to a solution of 5 g (18.92 mmol) of ethyl (3-(4-(aminoiminomethyl)phenyl)ureido)acetate in 53 ml of triethylamine and 100 ml of DMF. After 7 d at room temperature, solid is filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:36](OC(=O)C1C=CC(N)=CC=1F)[CH3:37]>>[CH2:36]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:34][CH3:35])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:37]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: CCOC(=O)c1ccc(N)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1F

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid, MS (ISP): m/e=519.0 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-fluoro-benzoic acid ethyl ester and yielded 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]1([CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]2[CH2:27][CH:26](OS(C)(=O)=O)[CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]2[CH2:27][CH:26]([O:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:25]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Oc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 8.6 g. (0.22 mole) of sodium amide in 100 ml. of dry toluene was added 18.2 g. (0.2 mole) of phenol in 50 ml. of dry toluene. After stirring for 2 hrs. at 60° C. the pot temperature was raised to 80° C. and a solution of 1-diphenylmethyl-3-methylsulfonyloxyazetidine (63.4 g., 0.2 mole) in 200 ml. of dry toluene was added dropwise. After an additional 2 hrs. at 80° C. the cooled mixture was treated with water, the toluene layer was extracted with dilute sodium hydroxide solution, dried and concentrated at reduced pressure. The residue was crystallized twice from a water-isopropanol mixture. The free base melted at 83°-85° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[C:36]([Cl:42])[C:37]([OH:41])=[C:38]([Cl:40])[CH:39]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3cc(Cl)c(O)c(Cl)c3)n2)c1

Procedure:
Intermediate 4 was coupled to 4-(2-Amino-ethyl)-2,6-dichloro-phenol by procedure F and the resulting product was deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 524. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.4 (m, 2H) 8.2 (d, 1H) 7.8 (d, 1H) 7.2 (s, 2H) 4.6 (s, 2H) 3.9 (m, 2H) 3.4 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.8 (m, 2H) 1.8 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8](=O)[CH2:9][CH3:10].[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20].BrCC=CC>O>[CH2:7]([O:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[F:12])[CH:8]=[CH:9][CH3:10]
Reactant: Oc1cccc(F)c1F
Reactant: CCC(C)=O
Agent: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC=CCOc1cccc(F)c1F
Temperature: 25 °C

Procedure:
122 g of anhydrous potassium carbonate was added to a 2-butanone (600 mL) solution containing 77.2 g of 2,3-difluorophenol, and then 90.0 mL of 1-bromo-2-butene (E/Z ratio=92/8) was added thereto. The solution was heated under reflux for 4 hours, then cooled to room temperature, and water was added dropwise thereto to stop the reaction. Extraction was performed with hexane (three times), and the collected organic phase was washed with 3M hydrochloric acid, water, saturated aqueous solution of sodium hydrogencarbonate, and saturated saline in this order, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure (155 to 160° C., 50 kPa), to thereby obtain 106 g of 1-(2-butenoxy)-2,3-difluorobenzene in the form of a colorless and transparent liquid (E/Z ratio=82/18 according to 1H-NM analysis).