Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:23](OCC)=[O:24])=[C:13]([SH:22])[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1.[NH2:29]OS(O)(=O)=O>O.O1CCCC1>[Br:6][C:7]1[C:16]([O:17][CH3:18])=[C:15]2[C:10]([C:11](=[O:28])[C:12]3[C:23](=[O:24])[NH:29][S:22][C:13]=3[N:14]2[CH:19]2[CH2:21][CH2:20]2)=[CH:9][CH:8]=1
Reactant: NOS(=O)(=O)O
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Br)ccc2c(=O)c3c(=O)[nH]sc3n(C3CC3)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of sodium bicarbonate (316.9 mg, 3.77 mmol) in water (7.5 mL) is added to a solution of ethyl 7-bromo-1-cyclopropyl-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (from above, ˜0.37 mmol) in tetrahydrofuran (7.5 mL) at room temperature. Hydroxylamine-O-sulfonic acid (214.7 mg, 1.90 mmol) is added as a solid and in one portion to this mixture. The resulting amber solution is stirred at room temperature for 2.5 h and quenched by addition of an aqueous solution of 5% hydrochloric acid (50 mL). The solid that formed is collected by filtration, washed with an aqueous solution of 5% hydrochloric acid (3×10 mL), washed with distilled water (3×10 mL), and dried in vacuo to give 17 as a tan solid. This product ids of sufficient purity (≧95% by 1H NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (DMSO-d6): δ 1.00 (m, 2H, c-Pr CH2), 1.20 (m, 2H, c-Pr CH2), 3.79 (s, 3H, OCH3), 3.85 (m, 1H, c-Pr CH), 7.66 (d, J=8.5 Hz, 1H, aromatic H-6), 7.93 (d, J=8.5 Hz, 1H, aromatic H-5), 11.67 (br, 1H). 13C{1H} NMR (DMSO-d6): δ 11.5 (c-Pr CH2), 35.1 (c-Pr CH), 61.9 (OCH3), 107.7, 122.9 (CH, C-5), 123.5 (C—Br, C-7), 127.9 (CH, C-6), 128.0 (C-4a), 136.5 (C-8a), 146.6 (C—OCH3), 164.5, 171.1 (C═O, C-4), 171.2 (br). LCMS m/z calcd for C14H1179BrN2O3S ([M]+) 366. Found 367 ([M+H]+). HRMS m/z calcd for C14H1179BrN2NaO3S 388.9571 ([M+Na]+). Found 388.9577.
Reaction SMILES: [CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[NH:15][C:13]1=[S:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(C(C)C)CC)(C)C.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([N:12]1[CH:19]=[C:18]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=2)[C:16](=[O:17])[N:15]=[C:13]1[S:14][CH2:44][C:43]1[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)[nH]c1=S
Reactant: Fc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCn1cc(Cc2cnc(OCC)nc2)c(=O)nc1SCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 1-undecyl-5-(2-ethoxypyrimidin-5-ylmethyl)-2-thiouracil (5.0 g) and diisopropylethylamine (2.1 ml) in dry methylene chloride (200 ml) was added 4-fluorobenzyl bromide (1.5 ml) and the mixture stirred under argon at room temperature for 20 h. The solution was washed with 5% aqueous sodium bicarbonate and the organic layer was added directly to a silica gel column (200 g). Elution with ethyl acetate to 5% methanol in ethyl acetate gave the desired product (2.7 g). 1H-NMR (CDCl3) δ0.8-0.95 (3H,m), 1.15-1.4 (16H,m), 1.43 (3H,t), 1.55-1.8 (2H,m), 3.68 (2H,s), 3.71 (2H,t), 4.41 (2H,q), 4.47 (2H,s), 6.86 (1H,s), 6.9-7.1 (2H,m), 7.3-7.45 (2H,m), 8.45 (2H,d); MS (APCI+) found (M+1)=527; C29H39FN4O2S requires 526.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:3])[CH3:2].C1N=C[N:34](C(N2C=NC=C2)=O)[CH:33]=1.CN>CN(C=O)C>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:34][CH3:33])=[O:10])=[CH:7][C:6]=1[C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1)=[O:15])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OC(C)C)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50° C. for 30 min. 5.2 mmol methylamine (41% aq solution) was then added, and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate) to afford the title compound. MS (m/e): 450.1 (M+H+, 100%)
Reaction SMILES: [CH3:1][N:2]([CH2:34][C@H:35]([OH:44])[C@@H:36]([OH:43])[C@H:37]([OH:42])[C@H:38]([OH:41])[CH2:39][OH:40])[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=4)=[C:22]([CH3:32])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:54](OCC)(=[O:56])C>ClCCl>[C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([N:2]([CH2:34][C@@H:35]([C@@H:36]5[C@@H:37]([C@H:38]([OH:41])[CH2:39][OH:40])[O:42][C:54](=[O:56])[O:43]5)[OH:44])[CH3:1])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:33])=[CH:21][C:22]=2[CH3:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)C[C@H](O)[C@H]4OC(=O)O[C@@H]4[C@H](O)CO)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-amide of Example 5 (0.190 g, 0.315 mmol), and N,N-diisopropylethylamine (0.110 mL, 0.315 mmol) were dissolved in anhydrous dichloromethane (6.3 mL) and the solution cooled to 0° C. N,N′-Carbonyldiimidazole (0.051 g, 0.315 mmol) was added and the reaction stirred at 0° C. for 1 hour, then warmed to room temperature and stirring continued for 12 hours. The solution was diluted with ethyl acetate and washed with water, 0.1 N hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification of the residue by flash column chromatography on silica gel eluting with ethyl acetate, afforded 0.140 g of the title compound as a white, partially crystalline solid, m.p. 166-175° C.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][CH:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C(#N)C>[NH2:2][C:3]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][I:20])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCC(I)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(N)(CCCCCCCCCCCCCCCCI)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diethyl 2-aminomalonate hydrochloride (2.116 g, 10.0 mmol) and caesiumcarbonate (7.100 g, 21.8 mmol, 2.2 eq.) were suspended in acetonitrile (50 mL) and stirred at r.t. for 15 min. Then diiodohexadecane 28 (5.017 g, 10.5 mmol, 1.1 eq.) was added and the mixture was refluxed for 6 h. After cooling to r.t. and partial evaporation of the solvent, the residue was purified by column chromatography (silica gel, 16×4 cm, cyclohexane/ethyl acetate, 2:1) to give the product as a yellowish oil. Yield: 3.097 g (56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][C:43](Cl)=[O:44])[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:43](=[O:44])[CH2:42][C:36]1[CH:35]=[C:34]([O:33][CH3:32])[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Product: COc1cc(CC(=O)N2CCc3ccccc3[C@@]2(c2ccccc2)[C@H](Oc2cc(OC)cc(OC)c2)C(=O)O)cc(OC)c1
Yield: 60.2 %

Procedure:
(±)-(S*)-(3,5-dimethoxy-phenoxy)-{(1S*)-2-[2-(3,5-dimethoxy-phenyl)-acetyl]-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl}-acetic acid (77 mg) is prepared in analogy to Example 5 starting from (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (90 mg, 0.214 mmol, Example 1) and 3,5-dimethoxyphenylacetyl chloride (83 mg, 0.385 mmol). LC-MS2: tR=5.23 min, [M+1]+=598.35, [M−1]−=596.29.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([O:11][C:21]([O:20][CH3:19])=[O:22])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 90 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 24 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 22 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1,3-bis (methoxycarbonyloxy)adamantane (yield 90%) was formed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1>S(Cl)(Cl)=O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]2[C:5]3[C:6](=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:10](=[O:12])[CH2:9]2)=[CH:14][CH:15]=1
Reactant: O=C(O)CC(c1ccc(F)cc1)c1ccc(F)cc1
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2ccc(F)cc2)c2ccc(F)cc21
Yield: 84.6 %

Procedure:
A solution of 850 grams of 3,3-bis(4-fluorophenyl)-propanoic acid in 600 milliliters of thionylchloride was refluxed for two hours and then concentrated in vacuo. The crude acid chloride was taken up in 2 liters of carbondisulfide. 850 grams of aluminiumchloride were added while stirring and cooling at a temperature of 10-15 degrees Centigrade. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured unto crushed ice, and one liter of concentrated hydrochloric acid was added. The mixture was extracted with methylene chloride, and the organic phase was extracted with water and 1 N sodium hydroxide solution. The organic phase was then dried over anhydrous magnesium sulfate, treated with active carbon and concentrated in vacuo. The residue was taken up in hot diisopropylether, an insoluble oil was separated by decanting, and the isopropylether extract was cooled. The crystals which separated out were sucked off and dried to give 670 grams of 3-(4'-fluorophenyl)-6-fluoro-1-indanone melting at 70-73 degrees Centigrade.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([Cl:12])=[C:9]([Cl:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[Cl:12]
Reactant: CCOC(=O)c1cc(Cl)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)s1
Temperature: 60 °C
Reaction time: 15 h
Yield: 39.4 %

Procedure:
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2 ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2-thiophenecarboxylic acid ethyl ester (5.27 g). 5-Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4,5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60° C. for 15 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2cccc(Br)c2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc(Br)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-bromo-phenyl)-thiazol-2-ylamine hydrobromide with 0.31 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.40 g of N-[4-(3-bromo-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:38])[C:21]([C:23]1[N:32]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]5[C:9]4=[O:18])=[CH:6][N:7]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: Nc1ccc(N2CCN3CCCCC3C2=O)cn1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCCC5C4=O)cn3)nc2n1C1CCCC1
Yield: 55.7 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g, 0.244 mmol) was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.072 g, 0.246 mmol, 1.01 eq) which gave 7-Cyclopentyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide, (0.070 g, 0.136 mmol) in 56% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.31-1.50 (m, 2H) 1.66-1.82 (m, 4H) 1.91 (br. s., 1H) 1.98-2.14 (m, 5H) 2.21 (td, J=11.42, 3.26 Hz, 1H) 2.40 (br. s., 1H) 2.58 (dd, J=12.30, 8.78 Hz, 2H) 2.67-2.81 (m, 2H) 2.93-3.07 (m, 2H) 3.16 (s, 7H) 3.47 (dd, J=11.29, 3.26 Hz, 1H) 4.02 (td, J=11.67, 4.77 Hz, 1H) 4.79 (dq, J=9.03, 8.87 Hz, 1H) 6.46 (s, 1H) 7.66 (dd, J=9.03, 2.51 Hz, 1H) 7.94 (s, 1H) 8.23 (d, J=2.01 Hz, 1H) 8.54 (d, J=9.03 Hz, 1H) 8.71 (s, 1H)
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:16][C:14]1[CH:13]=[CH:12][C:4]2[O:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:1][C:3]=2[CH:15]=1
Reactant: CCOC(=O)COc1ccc(C)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)ccc2o1
Temperature: 90 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-(2-formyl-4-methylphenoxy)acetate (2.24 g, 10.08 mmol) in 15 mL of DMF was added K2CO3 (2.79 g, 20.16 mmol), the mixture was stirred under nitrogen at 90° C. for 3 hr. After cooling to room temperature, the mixture was filtered through Celite, and washed with DCM. The combined filtrate was concentrated, and the resulting residue was purified by silica gel flash chromatography, 100% Heptane-20% Ethyl Acetate/80% Heptane, to give a white solid, ethyl 5-methylbenzofuran-2-carboxylate (1.2 g). LCMS retention time=1.54 minutes (LC method 3); MS (m+1)=204.8. 1H NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.1 Hz, 3H), 2.41 (s, 3H), 4.35 (q, J=7.1 Hz, 2H), 7.34 (dd, J=8.5, 1.4 Hz, 1H), 7.55-7.63 (m, 2H), 7.68 (d, J=0.9 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.C(Cl)Cl.O>[Cl:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=c1c2ccccc2sc2ccc(OCCCCl)cc12
Temperature: 25 °C
Yield: 66.9 %

Procedure:
30 g (0.13 mol) 2-hydroxythioxanthen-9-one was suspended in 350 mL acetone. 61.6 g (0.39 mol) 1-bromo-3-chloro-propane and 62.8 g (0.46 mol) potassium carbonate were added. The mixture was refluxed for 6 hours. The mixture was allowed to cool down to room temperature. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. The residue was suspended in a mixture of 300 mL ethyl acetate and 200 mL water. The precipitated residue was isolated by filtration and redissolved in a mixture of 100 mL methylene chloride and 50 mL water. Both the ethyl acetate fraction and methylene chloride fraction were isolated, pooled and dried over MgSO4. The solvent was removed under reduced pressure and 2-(3-chloropropoxy)-9H-thioxanthen-9-one was purified by preparative column chromatography on a Merck SVP D40 column, using a gradient elution from methylene chloride/hexane 30/70 to methylene chloride/hexane 50/50 at a flow rate of 40 mL per minute. 26.5 g of 2-(3-chloropropoxy)-9H-thioxanthen-9-one was isolated.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[OH:8][N:7]=[C:6]([Cl:11])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: Cc1ccc(C=NO)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(Cl)=NO)cn1

Procedure:
To a stirring mixture of 6-methylnicotinaldehyde oxime (500 mg, 3.67 mmol) in 4 mL DMF at room temperature, was added N-chlorosuccinimide (490 mg, 3.67 mmol) in roughly one tenth portions over 5 min. Additional N-chlorosuccinimide (175 mg, 1.31 mmol) was added after about 4 h. After a total of 6 h, the reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and filtered. The filtrate was passed through a short silica gel column eluted with EtOAc. The eluant was concentrated under vacuum to provide the title compound as a light brown solid. All of this was used in the next step without further purification. HPLC: retention time=0.44 min.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:1])[CH3:20])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1N
Yield: 72 %

Procedure:
To a solution of nickel (II) chloride hexahydrate (0.58 g, 2.5 mmol) and N,N-dimethyl-1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinamine (1.37 g, 4.90 mmol) in MeOH (25 mL) cooled to 0° C. was added NaBH4 (280 mg, 7.4 mmol) slowly to avoid foaming. When TLC indicated the consumption of starting material, the solution was concentrated to a purple residue. The purple residue was taken up in EtOAc and filtered through a pad of celite. The yellow filtrate was concentrated onto silica gel and purified by flash column chromatography to give the title compound of step B (0.88 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ 6.48-6.45 (m, 2H), 6.26 (dd, J=8.2 and 2.2 Hz, 1H), 4.17 (br s, 2H), 3.70 (s, 3H), 3.38 (d, J=12.4 Hz, 2H), 2.49-2.43 (m under DMSO peak, 2H), 2.16 (s, 6H), 2.11-2.04 (m, 1H), 1.78 (d, J=12.4 Hz, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][O:30][C:26]2[CH:25]=[C:24]([S:21]([C:18]3[CH:19]=[CH:20][C:14]4[CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[O:16][C:15]=4[CH:17]=3)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cccc(O)c4)cc3OC2C1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=S(=O)(c1cccc(OCC2CCOCC2)c1)c1ccc2c(c1)OC1CNCCC21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (enantiomer 2, 42 mg, 0.097 mmol) and 4-bromomethyl-tetrahydropyran (26 mg, 0.15 mmol) were dissolved in acetonitrile (1 ml). Cesium carbonate (95 mg, 0.29 mmol) was added, and the mixture was heated to 60° C. overnight. The solvent was evaporated and the residue purified by preparative TLC (30% EtOAc/hexane). The residue was dissolved in 1 mL of 4N HCl in dioxane (1 mL) and stirred for 2 h. The solvent was evaporated and the mixture was triturated with ether. The resulting solid was filtered, washed with ether (twice) and dried at 90° C. for 2 h. MS m/z 430 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.28-1.40 (m, 2H), 1.46-1.58 (m, 1H), 1.63-1.71 (m, 2H), 1.95-2.07 (m, 1H), 2.09-2.18 (m, 1H), 2.92-3.00 (m, 2H), 3.28-3.46 (m, 4H), 3.52-3.61 (m, 2H), 3.82-3.94 (m, 4H), 4.90-4.96 (m, 1H), 7.22-7.28 (m, 1H), 7.45 (s, 1H), 7.49-7.61 (m, 4H), 8.98 (s, 1H).