Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][Zn+])#[N:3].Cl[C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.Cl>CCOC(C)=O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[N:15]=[N:14][C:13]([NH:16][C:17](=[O:25])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)#[N:3]
Reactant: N#CCCCC[Zn+]
Reactant: O=C(Cc1ccccc1)Nc1ccc(Cl)nn1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Product: N#CCCCCc1ccc(NC(=O)Cc2ccccc2)nn1
Temperature: 19 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
A 1000 mL three-neck flask fitted with internal temperature probe and addition funnel was flushed with Ar(g). Under positive Argon pressure 4-cyanobutylzinc bromide (0.5M in THF, 500 mL, 250 mmol) was charged into the addition funnel then added to the reaction vessel at room temperature. Solid N-(6-chloropyridazin-3-yl)-2-phenylacetamide (20.6 g, 83.3 mmol) was added to the stirred solution at RT under Ar(g) flow, followed by the addition of NiCl2(dppp) (4.52 g, 8.33 mmol). The resulting mixture was stirred at 19° C. for 240 minutes and then quenched with ethanol (120 mL). Water (380 mL) added to the stirred red solution, giving a thick precipitate. Ethyl acetate (760 mL) added and stirred well for 30 minutes. The solids were removed by filtration through a pad of celite. The mother liquor was then transferred to a separatory funnel and the organic layer was washed with H2O (380 mL), 0.5% ethylenediaminetetraacetic acid solution (380 mL) and again with H2O (380 mL). The organic layer was concentrated by rotoevaporation. Resulting red oil was redissolved in EtOAc (200 mL) and 1M HCl (380 mL) was added to the well stirred flask. After 30 minutes the mixture was transferred to separatory funnel and the aqueous layer collected. The organic layer was extracted with 1M HCl (2×380 mL). The aqueous layer's pH was then adjusted to ˜7 using 7.5% sodium bicarbonate solution and the pale yellow precipitate was collected by suction filtration, rinsed with water (200 mL) and diethyl ether (2×200 mL). The solid was dried overnight under high vacuum to afford N-(6-(4-cyanobutyl)pyridazin-3-yl)-2-phenylacetamide (1023, 14.76 g). 1H NMR (300 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.23 (d, J=9.036 Hz, 1H), 7.59 (d, J=9.246 Hz, 1H), 7.32 (m, 5H), 3.79 (s, 2H), 2.90 (t, J=7.357 Hz, 2H), 2.56 (t, J=7.038 Hz, 2H), 1.79 (t, J=7.311 Hz, 2H), 1.63 (t, J=7.01 Hz, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:19])=[O:14])=[N:11][CH:12]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: OCc1ccc(OCc2cccc(Cl)c2)cn1
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)cn1

Procedure:
The mixture of 13.1 g of 5-(m-chloro-benzyloxy)-2-pyridinemethanol and 250 ml of water is stirred vigorously at 25°. To this mixture is added 11.5 g of potassium permanganate in several portions. Then the mixture is filtered, the precipitated manganese dioxide washed with hot water, the washing is combined with the filtrate, concentrated to a small volume and then acidified with aqueous hydrochloric acid. The precipitated product is collected and recrystallized from ethyl acetate to yield 5-(3-chloro-benzyloxy)-2-pyridinecarboxylic acid melting at 176°-177°.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@@H:11]([CH2:18][C:19]3[N:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]4[CH:34]=[C:33]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:32]=[CH:31][N:30]=4)[S:22][CH:23]=3)[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[O:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1>[ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C@@H:11]([CH2:18][C:19]3[N:20]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]4[CH:34]=[C:33]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH:32]=[CH:31][N:30]=4)[S:22][CH:23]=3)[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CCOC(=O)C[C@H](Cc1csc(CCCCNc2cc(N3CCOCC3)ccn2)n1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@H](Cc1csc(CCCCNc2cc(N3CCOCC3)ccn2)n1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(3S)-Ethyl 3-(1,3-benzodioxol-5-yl)-4-(2-{4-[(4-morpholin-4-ylpyridin-2-yl)amino]butyl}-1,3-thiazol-4-yl)butanoate hydrochloride (0.50 mmol) was dissolved in THF (2 mL) at 0° C. 1M LiOH (2.5 mL) was added, and the reaction was warmed to room temperature and stirred for 20 hours. The reaction was acidified to pH=1 with conc. HCl and concentrated in vacuo. The residue was purified via reverse phase HPLC using a gradient of 5–50% CH3CN/H2O/0.5% HCl over 30 minutes to obtain the desired product. Yield: 83 mg, 28% over 2 steps. 1H NMR (DMSO-d6) δ7.63–7.68 (m, 1H), 7.01–7.04 (m, 1H), 6.85–6.82 (m, 1H), 6.75–6.71 (m, 1H), 6.65–6.59 (m, 1H), 6.59–6.54 (m, 1H), 6.03–5.98 (m, 1H), 5.97 (s, 2H), 3.73–3.66 (m, 4H), 3.52–3.45 (m, 4H), 3.50–3.38 (m, 5H), 3.33–3.25 (m, 2H), 3.06–2.87 (m, 4H), 2.62–2.46 (m, 2H), 1.84–1.73 (m, 2H), 1.65–1.55 (m, 2H).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C([SiH](C(C)C)C(C)C)(C)C.[NH:18]([C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:57])[CH2:19][C:20]([NH:22][C@H:23]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:24][C:25]1[N:29]=[CH:28][N:27](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:26]=1)=[O:21]>O>[NH:18]([C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:57])[CH2:19][C:20]([NH:22][C@H:23]([C:49]([OH:51])=[O:50])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21].[F:4][C:3]([C:1]([OH:7])=[O:2])([F:6])[F:5]
Reactant: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OC(C)(C)C
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A mixture of TFA (206 ml), triisopropylsilane (10.8 ml), and H2O (10.8 ml) was added to N-palmitoyl-Gly-His(Trt)-OtBu (23.0 g, 30.8 mmol) while cooling with ice and the whole was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was washed with diisopropyl ether and then diethyl ether, and then collected by filtration with a membrane-filter. The residue was reprecipitated with TFA (35 ml) and diethyl ether (800 ml), and the precipitate was dried under reduced pressure to give 16.2 g (93%) of a target compound.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]>>[Cl:17][C:18]1[CH:23]=[C:22]([CH:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5](=[O:15])[CH2:6][CH2:7]2)[CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: Clc1ccccc1Cl
Reactant: Oc1cccc2ccccc12
Agent: [Al+3]
Agent: [Br-]
Solvent: O
Product: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 65 °C
Yield: 79.6 %

Procedure:
In a solution of 100 g (0.374 mole) of anhydrous aluminium bromide in 130 ml of orthodichlorobenzene, 28 g (0.194 mole) of α-naphthol are added. The green solution obtained is heated for 1 hour at 65° C. then hydrolysed with 400 ml of water at 40° C. After decantation, the organic phase is separated which is concentrated under a vacuum. After crystallization of the residue in 140 ml of methanol at 0° C. for 2 hours, 45 g of the expected compound are obtained after filtration and drying.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[NH:36]N>>[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1Cl
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1Cl

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and 2,3-dichloro-phenylhydrazine according to the method described for example 1. MS: M=515.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CN(C=O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1ccc(CS)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a stirred solution of 4-fluorobenzyl mercaptan (23.34 g, 164 mmol) in DMF (150ml) under argon, cooled in a bath at -2° C. as added portionwise 60% NaH in oil (6.57 g, 164 mmol) over 12 minutes. The mixture was then stirred at room temperature for 15 minutes before recooling in bath at -2° C. and adding by cannular, over 13 minutes, a solution of 4-bromo-1(tert-butoxycarbonyl)piperidine (10.84 g, 41.0 mmol) in DMF (50ml). The mixture was then stirred at room temperature for 24 h before partitioning between water (500ml) and diethyl ether (500ml). The aqueous layer was reextracted with more diethyl ether (500ml) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 10-15% EtOAc/hexane) to give 4.58 g (34%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.45 (9H, s), 1.49 (2H, m), 1.86 (2H, m), 2.67 (1H, m), 2.88 (2H, m), 3.73 (2H, s), 3.92 (2H, m), 6.99 (2H, t, J=8.6 Hz), 7.28 (2H, m). m/e (ES+) 326 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][CH2:23]1)=[O:21])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:19])[NH2:18])[CH:12]=1)(C)(C)C.C(OC([N:37]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([S:46]([OH:48])=[O:47])[C:40]=2[CH:39]=[CH:38]1)=O)(C)(C)C.[Li]>>[NH:37]1[C:45]2[C:40](=[C:41]([S:46]([NH:7][CH:8]([C:20]([N:22]3[CH2:23][CH2:24][CH:25]([CH3:28])[CH2:26][CH2:27]3)=[O:21])[CH2:9][CH2:10][C:11]3[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=3)[C:17]([NH2:18])=[O:19])(=[O:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(S(=O)O)cccc21
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NC(=O)OC(C)(C)C)CC1
Agent: [Li]
Product: CC1CCN(C(=O)C(CCc2cccc(C(N)=O)c2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 85 is prepared from [3-(3-carbamoyl-phenyl)-1-(4-methyl-piperidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester and lithum 1-(tert-butoxycarbonyl)-1H-indole-4-sulfinic acid in the same manner as Example 71. ESI MS Calc. 482.2; Found. 483.7 (M+H)+.
Reaction SMILES: Cl[Sn]Cl.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][N:6]=1>Cl>[NH2:12][C:8]1[CH:9]=[C:10]([Cl:11])[C:5]([Cl:4])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Product: Nc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous SnCl2 (300 g, 1.58 mol) and concentrated HCl (350 mL) were charged to a 5 L flask with mechanical stirrer and thermocouple. The flask was cooled in ice and the product of Example 2B (100 g, 0.518 mol) was added in portions maintaining the temperature below 65° C. After the addition was complete, the cold bath was removed, and the mixture was stirred for 2 hours at ambient temperature. The mixture was cooled in ice as 25% aqueous NaOH (1000 mL) was added to bring the mixture to pH>10. The mixture was extracted with CH2Cl2 (1×600 mL, 2×400 mL) and the combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated under vacuum. The residual solid was crystallized from a mixture of water (500 mL) and ethanol (100 mL) to provide the title compound as a solid. 1H NMR (CDCl3, 300 MHz) δ 3.80 (br s, 2H), 7.10 (d, J=3 Hz, 1H), 7.77 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 180/182/184 (M+NH4)+ 163/165/167 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.02 min; [M+H]+=393.34.
Reaction SMILES: C([O:4][CH:5]1[C:18]2[C:9](=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13]3)[CH2:8][CH2:7][CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][C:17]2[C:12]([CH:13]=1)=[N:11][CH:10]=[C:9]1[C:18]=2[CH:5]([OH:4])[CH2:6][CH2:7][CH2:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 1 %

Procedure:
To a solution of Compound 223 (1.425 g, 410 mmol) in MeOH (25 mL) was added solid K2CO3 (120 mg, 0.87 mmol) followed by stirring at 25° C. for three hours. The solvent was removed in vacuo, the residue was purified by passing through a short column (silica gel, elution with ethyl ether) to furnish Compound 224 (1.23 g, 98 percent): white crystalline solid; mp 155°-157° C. (from CH2Cl2 -Et2O); Rf =0.12 (silica, 33 percent ethyl ether in benzene); IR (CHCl3) νmax 3602, 2948, 1620, 1507, 1455, 1348, 1298, 1242, 1150 cm-1 ; 1H NMR (300 MHz, CDCl3) δ8.41 (s, 1 H, H6), 8.09 (d, J=9.2 Hz, 1 H, H1), 7.47 (d, J=6.9 Hz, 2 H, aromatic), 7.42-7.30 (m, 4 H, H4 and aromatic), 7.25 (dd, J=9.2, 2.9 Hz, 1 H, H2), 5.32 (t, J=3.5 Hz, 1 H, H10), 5.13 (s, 2 H, benzylic), 2.89-2.65 (m, 2 H, H7), 2.28-2.16 (m, 1 H, H8 or H9), 2.12-1.82 (m, 3 H, H8 or H9); MS (FAB+) m/e (rel intensity) 306 (M+H, 100), 290 (6); HRMS for C20H20NO2 (M+H), calcd 306.1494, found 306.1495. Anal. Calcd for C20H19NO2 : C, 78.66; H, 6.27; N, 4.59. Found: C, 78.80; H, 6.27; N, 4.50.
Reaction SMILES: C(NC1C=CC(S([N:14]=[N+:15]=[N-])(=O)=O)=CC=1)(=O)C.[O:17]=[C:18]([CH3:27])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC#N>[N+:14](=[C:19]([C:18](=[O:17])[CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N-:15]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-acetamidobenzenesulfonyl azide (1.5 ml) was added to a solution of tert-butyl 3-oxobutanoate (1.86 g, 10.12 mmol) and TEA (3.85 ml) in CH3CN (60 ml). The mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography to give tert-butyl 2-diazo-3-oxobutanoate as a yellow liquid (1.3 g, 77% yield).
Reaction SMILES: [Br:1][C@@H:2]1[C@H:9]([O:10][C:11](=[O:17])[NH:12][C:13](=[O:16])[CH2:14][Cl:15])[CH2:8][CH2:7][C@@:4]2([O:6][CH2:5]2)[C@@:3]1([OH:21])[C:18]([CH3:20])=[CH2:19].ClC1C=CC=C(C(OO)=[O:30])C=1.CCCCCC.C(OCC)(=O)C>ClCCl>[Br:1][C@@H:2]1[C@H:9]([O:10][C:11](=[O:17])[NH:12][C:13](=[O:16])[CH2:14][Cl:15])[CH2:8][CH2:7][C@@:4]2([O:6][CH2:5]2)[C@@:3]1([OH:21])[C:18]1([CH3:20])[CH2:19][O:30]1
Reactant: C=C(C)[C@@]1(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]12CO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1([C@@]2(O)[C@H](Br)[C@H](OC(=O)NC(=O)CCl)CC[C@]23CO3)CO1

Procedure:
By proceeding in accordance with the method of operation described in Example 2, starting from 2.14 g (5.6 mmol) of the crude compound obtained in Example 3 and 1.93 g (11.2 mmol) of 72% 3-chloroperbenzoic acid in 55 ml of dichloromethane, 0.9 g (2.26 mmol) of a mixture of the two expected diastereoisomers (73/27) is obtained in the form of a mousse after chromatography on silica gel twice (eluant: hexane/ethyl acetate, 3:1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28](O)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][C:49]=1[S:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)[NH2:46]>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:46][C:45]4[CH:47]=[CH:48][C:49]([S:50][CH2:51][C:52]5[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=5)=[C:43]([O:42][CH3:41])[CH:44]=4)=[O:29])=[CH:20][C:19]=3[CH:31]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCC)cc1
Reactant: COc1cc(N)ccc1SCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(OC)c2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (2 droplets) was added to the mixture, thionyl chloride (0.21 ml) was added to the mixture and the solution was stirred at room temperature for 1 hour. The solution was added dropwise to a solution of 3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]aniline (0.37 g) and triethylamine (2.96 ml) in THF (11.1 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 254) (0.50 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>>[C:30]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]([C:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([C:18]4[C:26]5[O:25][CH2:24][O:23][C:22]=5[CH:21]=[CH:20][C:19]=4[O:27][CH2:28][CH3:29])[C:12]=3[NH:11][CH:10]=2)=[O:8])[CH2:2]1)(=[O:33])[CH2:31][CH3:32]
Reactant: CCC(=O)Cl
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c13)OCO2
Product: CCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CC)C4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide (example A176) and propionyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc(OCc2ccccc2)c1Br
Yield: 95.5 %

Procedure:
To a solution of methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate (3.72 g, 10.59 mmol) in 1:1 MeOH/THF (50 mL) was added aqueous sodium hydroxide (1 M, 53.0 mL, 53.0 mmol). After 10 minutes the volatiles were removed under reduced pressure and the solution acidified to pH 1 by addition of concentrated hydrochloric acid resulting in formation of a thick white precipitate. The mixture was extracted with ethyl acetate (2×), and DCM (3×). The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to provide 3-(benzyloxy)-4-bromo-5-methoxybenzoic acid as a white solid (3.41 g). MS (M−1)=335.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.49 (m, 7H), 5.16 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: CC1CNC(C2C=CN=C(NC(=O)C3C=CC=CC=3)C=2)=N1.[CH2:22]([CH:25]1[CH2:29][NH:28][C:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:31]=2)=[N:26]1)[CH2:23][CH3:24]>>[CH2:22]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:36][C:37](=[O:44])[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:31]=2)[NH:28][CH:29]=1)[CH2:23][CH3:24]
Reactant: CCCC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Agent: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Product: CCCc1c[nH]c(-c2ccnc(NC(=O)c3ccccc3)c2)n1
Yield: 35 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide with N-(4-(4-propyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide, N-(4-(4-propyl-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained as a colorless solid in 35% yield: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 9.16 (br s, 1H), 8.69 (s, 1H), 8.11 (d, J=5.3 Hz, 1H), 7.88-7.82 (m, 2H), 7.70 (dd, J=5.3, 1.4 Hz, 1H), 7.56-7.49 (m, 1H), 7.48-7.37 (m, 2H), 6.87 (s, 1H), 2.54 (t, J=7.4 Hz, 2H), 1.69-1.55 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); MS (ES+) m/z 307.3 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][CH2:19][CH2:20]O>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:17][O:18][CH2:19][CH2:20][O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: COCCO
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COCCOCc1c2ccccc2cc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-methoxyethanol (1 l) in benzene (1.5 l), conc. sulfuric acid (3 ml) was added and the mixture was heated to 80° C. A solution of 9-anthracenemethanol (45 g, 0.22 mole) in 2-methoxyethanol (450 ml) was added to the mixture under reflux and stirring was continued for 1.5 hours under reflux. After standing at room temperature overnight, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried over anhydrous MgSO4 and evaporated. The residual crude oil (63 g) was chromatographed on silica gel (Wakogel C-200, manufactured by Wako Pure Chemical Industries, Ltd.) with n-hexane/ethyl acetate [50/1→25/1→8/1(V/V)] as eluent to give 47.6 g of 9-(2-methoxyethoxy)methylanthracene as orange yellow oil.