Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])[C:57]([OH:59])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:71][C:72]1[C:77](O)=[C:76]([F:79])[C:75]([F:80])=[C:74]([F:81])[C:73]=1[F:82].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH2:22][C@H:23]([N:28]([C:30](=[O:54])[C@H:31]([NH:46][C:47]([O:49][C:50]([CH3:52])([CH3:51])[CH3:53])=[O:48])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH3:29])[C:24]([O:26][CH3:27])=[O:25])[CH:16]=2)=[CH:11][C:10]=1[CH2:55][C@H:56]([NH:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])[C:57]([O:59][C:77]1[C:76]([F:79])=[C:75]([F:80])[C:74]([F:81])=[C:73]([F:82])[C:72]=1[F:71])=[O:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
0.89 g (crude product, about 0.922 mmol) of (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl}-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}-propionic acid (Example 20O) are introduced into 50 ml of dichloromethane. At −25° C., 0.85 g (4.61 mmol) of pentafluorophenol, 0.21 g (1.11 mmol) of EDC and 45 mg (0.37 mmol) of DMAP are added under argon. The mixture slowly warms to RT overnight. The reaction mixture is concentrated in vacuo and briefly dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].C([Li])CCC.Br[CH2:16][CH2:17][Cl:18].O>C(OCC)C>[CH3:1][C:2]1[CH:6]([CH2:16][CH2:17][Cl:18])[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9]
Reactant: ClCCBr
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(CCCl)C(C)=C1C
Temperature: 2 °C
Reaction time: 18 h

Procedure:
A 1-liter three-necked flask, provided with a dropping funnel, condenser, mechanical stirrer and nitrogen inlet, was charged with 30.5 g of 1,2,3,4-tetramethylcyclopentadiene (0.25 mol), dissolved in 700 mL of ethoxyethane, and cooled to 2° C. Then 160 mL of n-butyllithium (1.6 M in hexane; 0.26 mol) were added dropwise in two hours, followed by 18 hours of stirring at room temperature with the aid of a mechanical stirrer. Then 36.0 g of 1-bromo-2-chloroethane (0.25 mol) were added all at once. The reaction mixture was stirred at room temperature for 10 days. GC analysis of a sample showed that the conversion of the tetramethylcyclopentadiene was 91%. One hundred ml of water were added to the reaction mixture, followed by separation of the water phase and the organic phase. The organic layer was washed once with 50 mL of saturated aqueous sodium chloride solution, dried with sodium sulphate, filtered and boiled down. The residue (43.9 g) proved to have the following composition according to gas chromatography (GC) analysis: apart from the starting materials, 1-bromo-2-chloroethane (9 wt %) and 1,2,3,4-tetramethylcyclopentadiene (9 wt %). Only non-geminally coupled product (84%) and geminally coupled product (16%) were found to be present.
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl[C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30].C(N)(=[S:40])C>CN(C=O)C.C(OCC)(=O)C>[SH:40][C:24]1[C:25]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:26]=2[S:27][C:28]=1[C:29]([NH2:31])=[O:30]
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: CC(N)=S
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(S)c2c1
Temperature: 80 °C
Yield: 71 %

Procedure:
Diazabicycloundecene (DBU) (1.8 mL, 12.3 mmol) is added to a room temperature solution of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (1.0 g, 4.1 mmol) and thioacetamide (1.0 g, 13.1 mmol) in 10 mL of DMF. The mixture is warmed to 80° C. for 5.5 hours. The reaction mixture is allowed to cool and is diluted with ethyl acetate and washed with 1N HCl and water. The organic layer is extracted four times with 1N NaOH followed by water. The basic layers are combined and acidified with 6N HCl. The precipitate is filtered and washed with water. Recrystallization from ethyl acetate:hexane gives 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide in 71% yield; mp=205° C. dec.
Reaction SMILES: [C:1]12([CH2:11]OC3C(Cl)=CC(C(OC)=O)=CN=3)CC3CC(CC(C3)[CH2:2]1)C2.Cl[C:25]1[C:26]([O:36][CH2:37][C:38]23[CH2:48][C:42]4([F:49])[CH2:43][C:44]([F:47])([CH2:46][C:40]([F:50])([CH2:41]4)[CH2:39]2)[CH2:45]3)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[CH:11]1([C:25]2[C:26]([O:36][CH2:37][C:38]34[CH2:45][C:44]5([F:47])[CH2:43][C:42]([F:49])([CH2:41][C:40]([F:50])([CH2:46]5)[CH2:39]3)[CH2:48]4)=[CH:27][C:28]([F:35])=[C:29]([CH:34]=2)[C:30]([O:32][CH3:33])=[O:31])[CH2:1][CH2:2]1
Reactant: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Product: COC(=O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Yield: 62 %

Procedure:
Following the procedure as described in Example 150 step 3 and making variations as required to replace methyl 6-(adamantan-1-ylmethoxy)-5-chloronicotinate with methyl 5-chloro-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate. Purification by silica gel column chromatography (10:1 hexanes:ethyl acetate) gave the title compound as a colorless solid (0.57 g, 62%): 1H NMR (300 MHz, CDCl3) 7.49 (d, J=8.2 Hz, 1H), 6.51 (d, J=12.6 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 2H), 2.24-2.14 (m, 3H), 2.14-2.04 (m, 3H), 1.99-1.88 (m, 1H), 1.86-1.79 (m, 6H), 0.96-0.88 (m, 2H), 0.66-0.58 (m, 2H); MS (ES+) m/z 413.2 (M+1).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][C@@H:26]1[CH2:27][OH:28]>>[OH:28][CH2:27][C@H:26]1[CH2:29][CH2:30][CH2:31][N:25]1[C:3]([C:4]1[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[CH:8][CH:9]=1)=[O:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: OC[C@H]1CCCN1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC[C@@H]2CO)cn1
Yield: 96 %

Procedure:
As described for example 223, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using D-prolinol instead of L-prolinol, to the title compound (139 mg, 96%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]′.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)C1C=CC=CC=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCN(OC(=O)c2ccccc2)CC1
Reactant: CCCCCCCCc1ccc(I)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCl in THF (0.56 ml; 1.11 mmol) was added at −15° C. under N2, followed 1.27 M solution of anhydrous ZnCl2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at 0° C. The resulting mixture was stirred for 30 min on ice-bath under N2 and the solution of the product of Step B (0.16 g; 0.51 mmol) and CuCl2 (2.5 mol %) in anhydrous THF (10 ml) was added. The resulting mixture was allowed to warm up to room temperature and stirred for additional 10 min. This was diluted to 20 ml with Et2O and washed with 5% NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the title compound (0.06 g; 31%), as a creamy syrup. 1H-NMR (CDCl3) 7.07 (d, 2H, J=8.6 Hz); 6.84 (d, 2H, J=8.6 Hz); 3.55 (t, 4H, J=5 Hz); 3.06 (t, 4H, J=5 Hz); 2.51 (t, 2H, J=7.94 Hz); 1.55-1.38 (m, 11H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.93 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14](Cl)[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CO.CN(C)[CH:31]=[O:32]>O>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:10]=1[O:11][C:12]1[CH:13]=[C:14]([O:32][CH3:31])[CH:15]=[CH:16][C:17]=1[C:18]2=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(=O)c3cccc(OCc4ccccc4)c3oc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 5-benzyloxy-3-chloroxanthone (8.5 g.), sodium hydride (3 g.), methanol (20 ml.) and dimethylformamide (100 ml.) is stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is filtered. The residue is recrystallised from isopropanol to give 5-benzyloxy-3-methoxyxanthone, m.p. 158° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=[C:12]2[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:25][C:20]1[CH:19]=[C:18]([C:13]2[NH:14][C:15]3[C:11]([C:12]=2[CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]2=[O:38])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:23]=[C:22]([CH3:24])[CH:21]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-[5-benzyloxy-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]isoindole-1,3-dione (510 mg in 20 mL dry ethyl acetate was added 197 mg of 10% palladium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 37 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo to provide the crude title compound (418 mg).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH:25]1([NH:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:31]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:32]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNC1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(C3CCCCC3)c3cc(O)ccc23)c(O)c1
Yield: 24.7 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and cyclohexylhydrazine hydrochloride (0.150 g, 1.0 mmol) to give 0.040 g of product as a white solid
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:5]OCC)=O.[C:15]([CH2:17][C:18]([NH2:20])=[O:19])#[N:16].[OH-].[Na+]>CO>[CH3:1][C:2]1[NH:20][C:18](=[O:19])[C:17](=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:15]#[N:16]
Reactant: N#CCC(N)=O
Reactant: CCOC=C(C(C)=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Procedure:
The process according to claim 4 where 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone is reacted with cyanoacetamide in the presence of at least a molar equivalent quantity of sodium hydroxide per mole of cyanoacetamide in methanol and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:19][Si](C)(C)C>O1CCOCC1>[Br:19][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Br
Reactant: CS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
A solution of (4′-methanesulfonyl-biphenyl-4-yl)-methanol (129 mg, 0.49 mmol) in 1,4-dioxane (5 mL) was treated with bromotrimethylsilane (0.2 mL, 1.5 mmol) and stirred at 25° C. for 16 h. The reaction mixture was concentrated and purified by flash column chromatography to yield 4.15-B (152 mg, 95%) as a yellow solid. LCMS found for C14H14BrO2S (M+H)+: m/z=326.
Reaction SMILES: [OH:1][C@@:2]12[C:20](=[O:21])[O:19][C@@H:4]([C@H:5]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH:6]=[CH:7]1)[CH2:3]2.[OH-:22].[Li+]>C1COCC1.O>[OH:1][C@@:2]1([C:20]([OH:19])=[O:21])[CH:7]=[CH:6][C@@H:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C@H:4]([OH:22])[CH2:3]1
Reactant: [OH-]
Reactant: O=C1O[C@@H]2C[C@@]1(O)C=C[C@H]2OCc1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@]1(O)C=C[C@@H](OCc2ccc([N+](=O)[O-])cc2)[C@H](O)C1
Yield: 74 %

Procedure:
A solution of carbolactone VIII (28 mg, 0.10 mmol) in 1 mL of THF and 0.5 mL of a 0.5 M lithium hydroxide aqueous solution was stirred at room temperature for 1 hour. The resulting solution was diluted with milliQ water (5 mL) and treated with Amberlite IR-120 (H+) to pH 6. The resin was filtered and washed with milliQ water (15 mL). The filtrate was concentrated under reduced pressure to give 23 mg of acid IX (74%) in a pale solid yellow form. [α]25D−121° (c 1.1 in CH3OH); 1H-NMR (250 MHz, CD3OD, δ) 8.20 (d, 2H, J 8.8), 7.65 (d, 2H, J 8.8), 5.93 (dd, 1H, J 10.0 and 1.8), 5.73 (d, 1H, J 10.0), 4.84 (s, 2H), 4.04 (m, 1H), 3.93 (dt, 1H, J 7.9 and 1.8) and 2.07 (m, 2H); 13C-NMR (63 MHz, CD3OD, δ) 176.8, 147.6, 147.1, 130.4, 129.3, 128.1, 123.4, 81.1, 73.5, 70.4, 68.2 and 40.2; IR (KBr)/cm−1 3528 and 1596; EM-IQ+ (m/z) 310 (MH+); HRMS calculated for C14H16NO7 (MH+): 310.0928, 310.0928 found.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:19])[C:6]=2[C:5](Cl)=[CH:4][CH:3]=1.[SH:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[S:21][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:21][C:22]4[S:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)[CH:10]=[CH:11][C:12]=3[S:21][C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[C:7](=[O:19])[C:6]=2[C:5]([S:21][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:4][CH:3]=1
Reactant: Sc1nc2ccccc2s1
Reactant: O=C1c2c(Cl)ccc(Cl)c2C(=O)c2c(Cl)ccc(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(Sc3nc4ccccc4s3)ccc(Sc3nc4ccccc4s3)c2C(=O)c2c(Sc3nc4ccccc4s3)ccc(Sc3nc4ccccc4s3)c21
Yield: 90.2 %

Procedure:
The dyestuff used can be prepared as follows: 15 g of 1,4,5,8-tetrachloro-anthraquinone, 75 g of dimethylformamide, 35 g of 2-mercaptobenzthiazole and 30 g of potassium carbonate are heated to 125°-130° C for about 3 hours. After cooling, the dyestuff which has precipitated in attractive red prisms is filtered off and washed with methanol and water. After drying, 34 g of 1,4,5,8-tetra-(2-benzthiazolyl-thio)-anthraquinone = 90% of theory are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:2](=[O:1])[C:3]3[C:8]([O:9][C:10]=2[CH:11]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:18])[CH3:24]
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CCNCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A sample of compound 5a, (13.4 g, 55.6 mmol) was suspended in 220 mL CH2Cl2 and 24.4 mL (330 mmol) of thionyl chloride was added. The mixture was refluxed over 6 h, adding approximately 10 mL of additional thionyl chloride per hour until the reaction became homogeneous. At that time, the thionyl chloride and solvent were removed under vacuum and the remaining residue was diluted with an additional 220 mL CH2Cl2. To the suspension was added 100 mL ice cold 1.5 N NaOH, 100 mL CH2Cl2, and 17 mL (166 mmol) diethyl amine. After stirring for 15 min at room temperature, the phases were separated, and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to yield Compound 6a (14.7 g, 49.8 mmol). MS m/z(MH+)296.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[C:31]([CH3:33])N(C)[N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[CH:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[C:39](OCC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1N1CC2C(=CC=C(C(C)(C)C)C=2)C1=O)(=O)C.BrC1C=C(NC2C=CC=CN=2)C(=O)N(C)C=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:32]=[CH:31][CH:33]=[CH:39][N:29]=4)[C:24](=[O:35])[N:23]([CH3:36])[CH:22]=3)[C:16]=1[CH2:37][OH:38])[CH2:8]2)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(Nc2cc(-c3cccc(N4Cc5cc(C(C)(C)C)ccc5C4=O)c3CO)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: Cn1cc(Br)cc(Nc2ccccn2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccccn2)c1=O
Yield: 34 %

Procedure:
Using the same general procedure as described for the preparation of 105, reaction 103f (298 mg, 0.643 mmol) with 113a (150 mg, 0.536 mmol) gave a 34% yield (90 mg) of 113 as a white solid: mp 138-139° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, 1H, J=2.0 Hz), 8.58 (s, 1H), 8.17 (m, 1H), 7.73-7.71 (m, 2H), 7.62-7.56 (m, 2H), 7.50 (t, 1H, J=7.5 Hz), 7.44 (d, 1H, J=7.5 Hz), 7.39-7.37 (m, 2H), 7.28 (d, 1H, J=7.5 Hz), 6.78 (dd, 1H, J=6.5, 5.0 Hz), 4.94 (s, 2H), 4.89 (t, 1H, J=4.5 Hz), 4.34 (d, 2H, J=4.5 Hz), 3.60 (s, 3H), 1.65 (s, 9H); MS (ESI+) m/z 495.2 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O.[NH2:13][NH2:14]>C(O)CCC>[N:5]1([CH2:4][C:3]([NH:13][NH2:14])=[O:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: NN
Reactant: COC(=O)CN1CCOCC1
Solvent: CCCCO
Solvent: O
Product: NNC(=O)CN1CCOCC1
Yield: 68 %

Procedure:
As described for example 112a, morpholin-4-yl-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at 100° C. for 1 h. Evaporation of all volatiles and crystallization from n-butanol/toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.40 (m, 4H), 2.90 (s, 2H), 3.57 (m, 4H), 4.24 (s, 2H), 8.91 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) in MeOH (100 mL) was added a solution of 2.0 M CH3NH2 in MeOH (126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (300 mL), and NaBH4 (2-38 g, 62.8 mmole) was added. After 2 hrs the reaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). The aqueous solution was extracted with Et2O (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying in high vacuum left the title compound (10.1 g, 92%) as a faintly yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc(-c2cccc3ccc(O)nc23)cc1
Product: COC(=O)c1ccc(-c2cccc3ccc(Cl)nc23)cc1

Procedure:
A mixture of Example 336B (1.76 g, 6.3 mmol) in POCl3 (50 mL) was heated to reflux for 30 minutes and concentrated. The concentrate was purified through a silica gel pad with 4:1 hexanes/ethyl acetate to provide the desired product. MS (ESI) m/e 298 ( M+H)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.Cl[S:37]([NH2:40])(=[O:39])=[O:38].Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[S:37](=[O:39])(=[O:38])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][C:22]([C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:27]=[CH:26][CH:25]=4)=[N:23][C:16]=23)[CH2:13][C@@H:9]1[OH:8])[NH2:40]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@H]1CO
Reactant: NS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(=O)(=O)OC[C@@H]1C[C@@H](Oc2ccnc3[nH]c(-c4cccc5ccccc45)nc23)C[C@@H]1O
Reaction time: 0.02 h
Yield: 25.1 %

Procedure:
To a solution of ((1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{[2-(1-naphthyl)-3H-imidazo[4,5-b]pyridin-7-yl]oxy}cyclopentyl)methanol (0.0624 g, 0.000127 mol) in DMA (2.00 mL) was added chlorosulfonamide (0.0736 g, 0.000637 mol) and the mixture was stirred for 1.0 min. To this was added 12 M of hydrochloric acid in water (2.00 mL) dropwise at 0° C. and the mixture was stirred for 10 min. The mixture was added dropwise to 50 mL of a 2N Na2CO3 solution, and was extracted by CH2Cl2 (3×30 ml). The combined organic layers were concentrated and the residue was purified by flash chromatography (0 to 10% MeOH/EtOAc) to provide the title compound (14.5 mg, 25%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ: 8.49 (m, 1H,), 8.28 (m, 1H), 8.06 (d, 1H, J=8.3 Hz), 7.97 (m, 1H), 7.87 (dd, 1H, J=7.0 Hz, J=1.0 Hz) 7.63-7.54 (m, 3H), 6.89 (d, 1H, J=5.8 Hz) 5.40 (bs, 1H), 4.45 (dt, 1H, J=4.9 Hz, J=1.9 Hz), 4.35 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 4.19 (dd, 1H, J=7.2 Hz, J=2.5 Hz), 2.62 (m, 1H), 2.44-2.39 (m, 1H), 2.31-2.25 (m, 1H), 2.18-2.14 (m, 2H). LC/MS: Rt=1.55 min, E+ 455 (AA standard).