Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[C:4]=1[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:21]O>>[CH3:15][O:14][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:21])=[O:6]
Reactant: CO
Reactant: COc1cc(OC)c(C(=O)O)c(OC)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(OC)cc(OC)cc1OC
Temperature: 25 °C

Procedure:
2,4,6-trimethoxybenzoic acid (CAS 570-02-5) (5.61 g, 26.42 mmol) was suspended in 20 mL of methanol (CAS 67-56-1). Concentrated sulfuric acid (CAS 7664-93-9) (1 mL) was added to the mixture, and the reaction heated to reflux for 24 hrs. The reaction was cooled to room temperature, and the methanol (CAS 67-56-1) removed in vacuo. The residues were taken up in 50 mL 5% NaHCO3 (CAS 144-55-8) and extracted with hexane (CAS 110-54-3) until all the solids had dissolved. The hexane extract was dried over anhydrous Na2SO4 (CAS 7757-82-6), filtered, and rotovapped to dryness to give the desired product, methyl 2,4,6-trimethoxybenzoate (CAS 29723-28-2), as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[CH:8][CH:9]=[N:10][C:5]2=[C:4]([Cl:11])[N:3]=1.C1C(=O)N([I:19])C(=O)C1>C1COCC1>[I:19][C:8]1[CH:9]=[N:10][C:5]2[C:6]=1[NH:7][C:2]([Cl:1])=[N:3][C:4]=2[Cl:11]
Reactant: Clc1nc(Cl)c2nccc-2[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: Clc1nc(Cl)c2ncc(I)c-2[nH]1
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of 2,4-dichloro pyrrolo[3,2-d]pyrimidine 19 (100 mg, 0.53 mmol) in anhydrous THF (5 mL), NIS (144 mg, 0.64 mmol) was added under N2 atmosphere and stirred for 2 h after which TLC indicated consumption of 19. The solvent was removed in vacuo and the residue dissolved in EtOAc. The organic phase was washed with aq. solution of Na2S2O3 followed by water, brine and then dried over MgSO4. The organic layer was concentrated in vacuo and loaded on silica. The product 20 was purified using column chromatography eluting with 9:1 hexanes/EtOAc to obtain product as off-white solid (90 mg, 54%). Rf 0.55 in 3:1 hexanes/EtOAc. Mp decomposed from 160-230° C. 1H NMR (400 MHz, DMSO-d6): δ 8.29 (s, 1H), 13.19 (s, 1H, NH). 13C NMR (400 MHz, DMSO-d6): δ 58.2, 124.4, 140.9, 143.5, 149.8, 153.5. ESI-MS m/z for calculated [M+H]+ 313.8743. found 313.8740.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C([Li])CCC.CCCCCC.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[C:30]1[C:31](=[O:37])[CH2:32][CH2:33][C:34]=1[O:35][CH3:36].[O:38]1[CH2:43][CH2:42][CH:41]([CH:44]=[O:45])[CH2:40][CH2:39]1>C1COCC1>[OH:45][CH:44]([CH:41]1[CH2:42][CH2:43][O:38][CH2:39][CH2:40]1)[CH:32]1[C:31](=[O:37])[C:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])=[C:34]([O:35][CH3:36])[CH2:33]1
Reactant: O=CC1CCOCC1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To a solution of N-ethyl-N,N-diisopropylamine (527 μl, 3.76 mmol) in THF (5 ml) under N2 at −78° C. is added, dropwise, a 2.5M solution of butyllithium in hexane (1.32 ml, 3.3 mmol) and the reaction allowed to stir at −78° C. for 20 minutes. This pale yellow solution is then added dropwise, over a period of 10 minutes, to a solution of 2-(2,4,6-trimethylphenyl)-3-methoxy-cyclopent-2-enone (691 ml, 3 mmol) in THF (5 ml) under N2, which is pre-cooled to −78° C. The resulting solution is allowed to stir at −78° C. for 40 minutes. A solution of tetrahydropyran-4-carbaldehyde (377 mg, 3.3 mmol) in THF (1 ml) is then added in one portion, the reaction mixture is stirred at −78° C. for 30 minutes before being allowed to warm to room temperature over a period of 60 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organics were purified by flash chromatography to give 5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (648 mg).
Reaction SMILES: FC(F)(F)C1C=CC(N2C=NC(C3C=CC(C[CH2:21][C:22](N=[N+]=[N-])=[O:23])=CC=3)=N2)=CC=1.[N:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[C:30]=[O:31].[CH:55]([C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:59]=1[NH:66][C:67]([NH2:69])=[S:68])([CH3:57])[CH3:56]>>[CH:55]([C:58]1[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][C:59]=1[N:66]1[C:22](=[O:23])[CH2:21][S:68]/[C:67]/1=[N:69]\[C:30]([NH:29][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[O:31])([CH3:57])[CH3:56]
Reactant: [N-]=[N+]=NC(=O)CCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: COc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: O=C=NCCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1
Product: COc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(C(F)(F)F)cc4)n3)cc2)c1

Procedure:
The title compound was prepared as described in Example 35 using 3-(4-(1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propanoyl azide/3-(4-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C35b) and 1-(2-isopropyl-5-methoxyphenyl)thiourea (CA40) and isolated as a brown foam (0.040 g, 30%).
Reaction SMILES: COC1C=CC(O)=C(C2OC3C=CC=C(CNCC4C=CC=CN=4)C=3N=2)C=1.[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[C:41]=3[N:42]=2)=[C:32]([O:56]COC)[CH:31]=1>>[CH3:28][O:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][C:33]([C:38]2[O:39][C:40]3[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)[C:41]=3[N:42]=2)=[C:32]([OH:56])[CH:31]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC

Procedure:
2-(4,5-dimethoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F26) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F23) using 2-(4,5-dimethoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F17) (100 mg, 0.23 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) in 92% (83 mg); 1H-NMR (500 MHz, CDCl3) δ3.95 (s, 3H), 3.96 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 6.66 (s, 1H), 7.17 (dd, 1H, J=7.5, 5.0 Hz), 7.31 (t, 1H, J=8.0 Hz), 7.37–7.40 (m, 2H), 7.41 (s, 1H), 7.48 (d, 1H, J=8.0 Hz),7.67 (t, 1H, J=7.5 Hz), 8.66 (d, 2H, J=5.0 Hz), 11.27 (s, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15](=[O:24])[CH2:16][O:17][C@H:18]1[CH2:22][CH2:21][C@H:20]([NH2:23])[CH2:19]1)([CH3:13])([CH3:12])[CH3:11].Cl[C:26]1[C:27]2[C:34]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[C:33]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[O:32][C:28]=2[N:29]=[CH:30][N:31]=1.O>CN(C=O)C>[C:10]([O:14][C:15](=[O:24])[CH2:16][O:17][C@H:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:26]2[C:27]3[C:34]([C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[C:33]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[O:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:19]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@@H]4CC[C@H](OCC(=O)OC(C)(C)C)C4)c23)cc1
Temperature: 100 °C

Procedure:
Add 0.86 ml (5 2 mmol) of diisopropylethylamine to a mixture of 560.4 mg of (+/−)-cis/trans-[(3-aminocyclopentyl)oxy]acetic acid tert-butyl ester (crude product, approx. 2.60 mmol) and 964.3 mg (2.86 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 2.0 ml of DMF. Heat the reaction mixture to 100° C. for 6 h. After cooling, add water and extract with dichloromethane. Wash the organic phase with satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, dry over sodium sulphate and concentrate under reduced pressure. After drying under high vacuum, purify the product mixture by preparative RP-HPLC (eluent: acetonitrile/water gradient) and separate it into the cis/trans isomers.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@:5]2([OH:22])[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[O:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:4]2[CH2:3]1.[CH3:23][I:24]>C1(C)C=CC=CC=1.CCOCC.CO>[I-:24].[OH:22][C@@:5]12[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[O:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:4]1[CH2:3][N+:2]([CH3:23])([CH3:1])[CH2:7][CH2:6]2
Reactant: CI
Reactant: Cc1cccc2c1Oc1ccccc1[C@@]1(O)CCN(C)C[C@@H]21
Solvent: CCOCC
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cccc2c1Oc1ccccc1[C@@]1(O)CC[N+](C)(C)C[C@@H]21
Product: [I-]

Procedure:
5.0 g (17 mmol) of the compound of Example 1 were dissolved in a mixture of 200 ml of toluene, 100 ml of ether and 50 ml of methanol. While stirring 50 ml of methyl iodide were added at room temperature. After 24 hrs crystals had formed. The mother liquor was filtered off and the crystals collected. This gave 6.75 g (91%) of the quaternary iodide. m.p. >260° C. (dec.).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:9](=C[CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](Cl)(=[O:16])[C:13](Cl)=O.C(=O)([O-])[O-].[NH4+:22].[NH4+:23]>C(OCC)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:11][N:22]=2)[C:6]([CH2:13][C:12]([NH2:23])=[O:16])=[CH:7]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: [NH4+]
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: NC(=O)Cc1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 5-methoxyindole (2.50 g, 17.0 mmol) in 50 mL of anhydrous diethyl ether cooled to 0° C. was added oxalyl chloride (1.63 mL, 18.68 mmol) and subsequently warmed to room temperatue. After 3.5 hours the solution was cooled to 0° C. and 50 mL of an aqueous solution of ammonium carbonate was added. After stirring overnight the precipitate was filtered off and washed with water, isopropanol and diethyl ether to afford the desired acetamide in 78% yield as a bright yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:20])/[CH:16]=[C:17](\[NH2:19])/[CH3:18])[CH3:13].[CH2:21]([O:23][C:24](=[O:33])[CH2:25][C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=O)[CH3:22]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:25]([C:24]([O:23][CH2:21][CH3:22])=[O:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:19][C:17]=1[CH3:18])=[O:20])[CH3:13]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(C)N1
Yield: 62 %

Procedure:
15 g of 3-nitrobenzaldehyde, 13 g of β-aminocrotonic acid ethyl ester and 19 g of oxalacetic acid diethyl ester in 60 ccs of ethanol are heated to the boil overnight. The green-yellow crystals obtained, in 62% yield, after cooling, melt at 123°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6](I)[CH:5]=[CH:4][C:3]=1[F:10].[CH2:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1)[CH2:12][CH3:13].Cl>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:11][CH2:12][CH3:13])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[F:10]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1ccc(I)c(F)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2cc(F)c(Br)c(F)c2)cc1
Temperature: 5 °C
Yield: 57.1 %

Procedure:
2-Bromo-1,3-difluoro-4-iodobenzene (20 g) was dissolved in diethylamine (30 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.06 g) and copper(I) iodide (0.06 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-propylphenylacetylene (10 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (15 ml) and ice (30 g). After extraction with chloroform, the resultant was washed twice with water, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 185° to 192° C./4 mmHg), and then recrystallized from a mixed solvent of acetone and methanol to give 4-bromo-3,5-difluoro-4'-propyltolane (12 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:43]C)[CH2:40][CH2:41]O)[CH3:38]>N1C=CC=CC=1>[CH2:37]([N:39]([CH2:40][CH3:41])[CH2:43][CH2:26][O:28][C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])=[O:35])[CH3:38]
Reactant: CCN(CC)CCO
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCN(CC)CCOC(=O)Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 70 °C
Reaction time: 18 h
Yield: 27.9 %

Procedure:
A mixture of Example 294 (36.7 mg, 0.11 mmol), triphosgene (10.4 mg, 0.033 mmol), and pyridine (1 mL) was stirred for 3 hours at 70° C., treated with 2-(diethylamino)ethanol (70 μL, 0.53 mmol), stirred for 18 hours at 70° C., concentrated, and purified by Cl18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (4.5 mg, 9%). MS (ESI(+)) m/e 490 (M+H)+; MS (ESI(−)) m/e 488 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.04 (d, 1H), 7.74 (dd, 1H), 7.64 (m, 1H), 7.24 (t, 1H), 6.97 (d, 1H), 6.65 (m, 1H), 4.40 (t, 2H), 3.20 (q, 6H), 2.56 (m, 4H), 1.66 (m, 4H), 1.20 (t, 6H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](OCC2C=CC=CC=2)=O)[CH2:13][C@@H:12]1[C:27](O)=O)=O)C1C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][C:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH:36]2>>[ClH:30].[ClH:30].[Cl:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][C:37]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[C:36]2[CH2:27][C@H:12]1[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][N:11]1[CH3:9]
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Reactant: Clc1cccc2cc(-c3ccccc3)[nH]c12
Product: CN1CCN(C)[C@@H](Cc2c(-c3ccccc3)[nH]c3c(Cl)cccc23)C1
Product: Cl

Procedure:
By substantially following the procedures of Example 1, utilising di-N-benzyloxycarbonylpiperazine-2(R)-carboxylic acid in place of N-benzyloxycarbonylnipecotic acid and 7-chloro-2-phenylindole in place of 2-phenylindole, was prepared the title compound as a white solid. (Found: C, 57.69; H, 6.11; N, 9.56; C21H24Cl3N2.0.6H2O requires C, 57.64; H, 6.27; N, 9.60%); mp 260° C. (from EtOH); [α]D22+25.2 (c 1.0 in MeOH); δH (400 MHz; D2O) 2.38 (4H, m, CH3 and aliphatic), 2.58 (3H, s, CH3), 2.70-2.88 (5H, m, aliphatics), 3.16-3.21 (2H, m, aliphatics), 3.50 (1H, m, aliphatic), 7.19 (1H, t, J 7.9 and 7.8, indole H5), 7.32 (1H, dd, J 7.6 and 0.6, indole H6), 7.51-7.55 (1H, m, aromatic), 7.57-7.63 (8H, m, aromatics); m/z (ES30) 353 (M++H, 100%).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: BrBr
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a 100 mL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CCl4 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0° C. and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CCl4 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0° C. for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% Na2S2O3 solution, saturated NaHCO3 solution and brine (2×). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z=287.8, 289.8, 290.8−ve. 1H NMR (400 MHz, CDCl3) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.FC(F)(F)C(O)=O.[OH-].[Na+].[Br:26][CH2:27][CH2:28]O>>[Br:26][CH2:27][CH2:28][O:16][CH:14]1[C:15]2[C:10](=[N:9][C:8]3[C:3]([C:2]=2[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12][CH2:13]1
Reactant: OCCBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Nc1c2c(nc3ccccc13)CCCC2OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a suspension of 9-amino-1,2,3,4-tetrahydroacridin-1-ol (7.55 g) in 40 ml of 2-bromoethanol was added 9.9 ml of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 18 hrs, added to iced sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate →2% triethylamine/ethyl acetate) to give 7.6 g (67%) of a product. Recrystallization from methanol/water gave the analytical sample, mp 163.5°-164.5° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[CH:11]1.C1(C)C=CC=CC=1>>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:16])/[CH:11]=[CH:12]\[C:13]([O-:15])=[O:14].[C:10]([O-:15])(=[O:16])/[CH:11]=[CH:12]/[C:13]([O-:9])=[O:14]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)/C=C\C(=O)[O-]
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
A mixture of octan-1-ol (250 ml, 1.59 mole) and toluene (200 mls) was placed in a 1-liter 3-necked round bottomed flask fitted with stirrer and condenser. Maleic anhydride (153 g, 1.56 mole) was added and the mixture was stirred under reflux for 2 hours. The toluene was evaporated in vacuo and the resulting oil diluted with 30/40 petroleum ether (1.5 liters). The mixture was filtered and left to crystallise at 4° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Cl:22][C:23]1[C:32]([CH2:33][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)=[N:31][C:30]2[NH:29][C:28](=[O:35])[CH2:27][S:26][C:25]=2[CH:24]=1
Reactant: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CSc2cc(Cl)c(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 10 mL of a chloroform solution containing 325 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 234 mg of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 64 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 367 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 478 mg of 1-(2-(4-((7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH2:40][CH:41]2[CH2:42][CH2:43]2)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:21])[CH3:22])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CCN(C(=O)[C@H](CN(CC4CC4)C(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
(5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.0444 g, 0.1445 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.05114 g, 0.1445 mmol) were combined in methylene chloride (1.25 mL). They were then treated with diisopropylethylamine (0.07552 ml, 0.4336 mmol), followed by HBTU (0.05495 g, 0.1445 mmol). The reaction was stirred at ambient temperature for 16 hours. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was chromatographed on SiO2 (Biotage 12M) and eluted with 4% MeOH/MC. The material was concentrated in vacuo to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (67.4 mg, 82%). LCMS (APCI+) [M+H]+ 570.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[K+]>O.CO.CCO>[NH2:15][C:11]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: NO
Reactant: O=[N+]([O-])c1cccc2ncccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2cccnc12
Temperature: 55 °C

Procedure:
To a five liter round bottom flask fitted with an air stirrer, condenser, addition funnel, thermometer and hot water bath were charged 40 g. (0.23 mole) 5-nitroquinoline and 100 g. (1.44 mole) hydroxylamine hydrochloride. Then 1950 ml. of 95% EtOH was added and the solids dissolved after which 200 g. KOH in 1200 ml. MeOH was added over a 50 minute period at 54°-57° C. The mixture was allowed to stir at 55° C. for an additional hour and then dumped into ten liters of water, allowed to cool and filtered. An orange solid was crystallized out of 95% ethanol. Such product was 8-amino-5-nitroquinoline.