Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([NH:26][O:27]CC4C=CC=CC=4)=[O:25])=[CH:20][CH:19]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>[Pd].CO.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([NH:26][OH:27])=[O:25])=[CH:22][CH:23]=3)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A mixture of 4-{[(benzyloxy)amino]carbonyl]phenyl 1-(4-methoxyphenyl) cyclohexanecarboxylate (22a) (0.072 g, 0.16 mmol) and 5% palladium on activated carbon (0.054 g) in methanol (1 ml) was hydrogenated at room temperature until the starting material disappeared (ca. 45 minutes). The black suspension was filtered, the catalyst was washed with methanol (3×1 ml), and the filtrate was evaporated to give a white solid. The solid was suspended in diethyl ether (3 ml) and the mixture was intensively stirred overnight. The solid was filtered, washed with diethyl ether (1 ml), and dried in vacuum to give the title compound (0.037 g, 64%) as white crystals, m.p. 127-129° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.18-1.90 (8H, m); 2.36-2.65 (2H, m, overlapped with a signal of DMSO); 3.76 (3H, s); 6.97 (2H, d, J=8.6 Hz); 7.01 (2H, d, J=8.8 Hz); 7.40 (2H, d, J=8.8 Hz); 7.77 (2H, d, J=8.6 Hz); 9.07 (1H, br s); 11.23 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 2.2% (column size 3.9×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 230 nm; sample concentration 0.3 mg/ml; flow rate 1.0 ml/min). Anal. Calcd for C21H23NO5*0.3H2O, %: C, 67.29; H, 6.35,; N, 3.74. Found, %: C, 67.29; H, 6.23; N, 3.76.
Reaction SMILES: [C:1]([CH2:5][N:6]1[CH2:23][CH2:22][N:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[C:14]3[CH:8]2[CH2:7]1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:2][CH2:1][CH2:5][N:6]1[CH2:23][CH2:22][N:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[C:14]3[CH:8]2[CH2:7]1
Reactant: COC(=O)CN1CCN2c3ccccc3Cn3cccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCN1CCN2c3ccccc3Cn3cccc3C2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To the solution of 780 mg of 2-carbomethoxymethyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 20 ml of tetrahydrofuran, 150 mg of lithium aluminum hydride are added and the mixture is stirred for 2 days at room temperature. It is combined with 0.15 ml of water, 0.15 ml of 15% aqueous sodium hydroxide and 0.15 ml of water in this order filtered and the filtrate evaporated, to yield the 2-(2-hydroxyethyl)-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, which is converted into its mono-fumarate melting at 187°-189° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)[C:9]2[C:10]([C:16](O)=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH3:15])[C:13]=3[CH3:14])[C:16](=[O:17])[N:19]2[C:20]2[CH:25]=[C:24]([CH3:26])[C:23](=[O:27])[N:22]([CH3:28])[CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C)c2C)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C)c(C)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylic acid (Step 28.4). tR: 3.62 min (HPLC 1); tR: 0.81 min (LC-MS 2); ESI-MS: 383 [M+H]+ (LC-MS 2); Rf=0.55 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 2.05 (s, 3H) 3.35 (s, 3H) 3.83 (s, 3H) 6.10 (s, 1H) 7.24 (d, J=8.6 Hz, 2H) 7.33-7.41 (m, 3H) 7.72 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH2:38][NH:37][S:34]([C:30]2[CH:29]=[C:28]([NH:27][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)=[O:13])[CH:33]=[CH:32][CH:31]=2)(=[O:36])=[O:35])=[CH:45][CH:44]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCCc2ccncc2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-pyridin-4-yl-ethyl)-benzenesulfonamide (example B.7) according to general procedure II. Yellow solid. MS (ISP) 633.0 [(M−H−]; mp 236° C.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][O:4][N:3]1[C:13](Cl)=[O:14].[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18]>ClCCl>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:13]([N:3]1[O:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:2]1[CH3:1])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCNCC=C
Reactant: CC1c2ccccc2CCON1C(=O)Cl
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)N1OCCc2ccccc2C1C

Procedure:
A solution of 2.6 g. of 88 percent 1-methyl-1,2,4,5-tetrahydro-3,2-benzoxazepine-2-carbonyl chloride in 20 ml. of dichloromethane was added at room temperature to a solution of 2.23 g. of diallylamine in 30 ml. of dichloromethane. The mixture was then refluxed for two hours and after cooling was washed sequentially with aqueous 5 percent HCl, with aqueous sodium bicarbonate and with water. The organic layer was dried over Na2SO4 and evaporated to dryness. The residue was distilled at 140° C./0.02 mm Hg. Yield 2.3 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]2([CH3:56])[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[C:34](=[O:35])[C:33]([CH3:53])([CH2:36][CH2:37][C:38]4[CH:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]([OH:48])=[C:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:39]=4)[NH:32][C:31]3=[O:54])[C:19]2=[O:55])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65].Cl>CN(C)C=O.O>[C:44]([C:42]1[CH:43]=[C:38]([CH2:37][CH2:36][C:33]2([CH3:53])[N:32]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:31](=[O:54])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:20]3[C:19](=[O:55])[C:18]([CH3:56])([CH2:17][CH2:16][C:7]4[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=4)[N:22]([CH2:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8])[C:21]3=[O:23])[C:34]2=[O:35])[CH:39]=[C:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]=1[OH:48])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC1(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)NC(=O)N(CCCCCCN2C(=O)NC(C)(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)C1=O
Reactant: CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCN1C(=O)N(CCCCCCN2C(=O)N(CCCCCC)C(C)(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)C(=O)C1(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
7.75 g (0.01 mol) of 3,3'-hexamethylene-bis-[5-(3",5"-di-tert-butyl-4"-hydroxyphenylethyl)-5-methylhydantoin] is added portionwise with stirring to a slurry of 1.92 g (0.04 mol) of a 50% dispersion of sodium hydride in mineral oil in 100 g of dry dimethylformamide. The temperature of the reaction mixture is maintained at 50°-55° C until gas evolution ceases. 3.3 g (0.02 mol) of 1-bromohexane is then added dropwise over a period of 15-30 minutes. The temperature of the mixture is maintained between 60°-80° C until the reaction is complete. The reaction mixture is then poured into water and neutralized with dilute hydrochloric acid. The mixture is then extracted with chloroform. The chloroform phase is dried and completely concentrated under reduced pressure to yield as the residue the desired 3,3'-hexamethylene-bis[5-(3",5"-di-tert-butyl-4"-hydroxyphenylethyl)-5-methyl-1-n-hexylhydantoin].
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([NH:7][CH2:8][CH2:9][N:10]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:11][C:12](OCC)=[O:13])=[CH:5][CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+]>C(#N)C.CO.O>[C:1]([C:3]1[CH:24]=[CH:23][C:6]([N:7]2[CH2:8][CH2:9][N:10]([CH2:17][C:18]([OH:20])=[O:19])[CH2:11][C:12]2=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CN(CCNc1ccc(C#N)cc1)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(CC(=O)O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A suspension of Ethyl 2-[2-(4-cyanoanilino)-ethyl (2-ethoxy-2-oxoethyl)amino]acetate (58 g, 0.174 mol), diisopropylethylamine (4 g, 0.03 mol) and potassium carbonate (24 g, 0.174 mol) in 400 ml of acetonitrile is refluxed for 2 days. The mixture is filtered and rinsed with dichloromethane. The filtrate is evaporated to give a brown solid, which is dissolved in 150 ml of methanol and 50 ml of water, and lithium hydroxide monohydrate (8.4 g, 0.2 mol) is then added. After stirring for 30 minutes at room temperature, half of the methanol is removed under vacuum to give a suspension. About 100 ml of water are added and this mixture is acidified at 5° C. The product is filtered off, rinsed with water and dried under vacuum at 50° C. to give 27.2 g of a beige-coloured powder.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][NH:36][S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]3[CH2:51][CH2:50][N:49](C(=O)C(F)(F)F)[CH2:48][CH2:47]3)=[CH:42][CH:41]=1)(=[O:39])=[O:38])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][CH3:10])[O:4][C@H:3]1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH2:35][NH:36][S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH:46]3[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]3)=[CH:42][CH:41]=1)(=[O:38])=[O:39])=[N:15][C:16]=2[NH:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)nc32)[C@H](O)[C@@H]1O
Agent: N
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccc(C5CCNCC5)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 78.8 %

Procedure:
The title compound was prepared by a similar method to example 20 using N-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-4-[1-(2,2,2-trfluoroacetyl)-4-piperidinyl]benzenesulfonamide (0.26 g, 0.32 mmol) (example 21) and a saturated methanolic solution of ammonia (20 ml). This gave the title compound (180 mg) as a solid. MS: 715 (MH+)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>ClCCl>[O:5]1[CH2:6][CH2:7][CH:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:3][CH2:4]1
Reactant: OC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 4-hydroxytetrahydropyran (4.5 g, 44 mmol) (Aldrich) in dichloromethane (90 mL) at 0° C. was added triethylamine (5.4 g, 53 mmol), and methanesulfonyl chloride (3.73 mL, 48 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 1 h, then at room temperature for 1.5 h. The mixture was poured into water, extracted with dichloromethane. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated to give crude methanesulfonic acid tetrahydropyran-4-yl ester as a white solid (Yield 8 g, 100%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:13]/[CH:14]=[CH:15]\[CH2:16]Br.O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([N:9]1[CH2:16][CH:15]=[CH:14][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC/C=C\CBr
Reactant: NC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)N1CC=CC1
Temperature: 40 °C

Procedure:
121 g (1 mol) of benzamide in 3 l of toluene are introduced initially, 200 g of powdered potassium hydroxide are introduced with stirring, 32 g (0.1 mol) of tetrabutylammonium bromide are added and the mixture is heated to 40° C. 243 g (1 mol) of 88% cis-1,4-dibromo-2-butene are then added dropwise in such a way that the internal temperature does not exceed 60° C. The mixture is stirred for another 5 hours at 50° C., then poured into water, and the organic phase is separated off, washed with water, dried and concentrated. The residue is distilled under reduced pressure.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=O)=[CH:19][CH:18]=1)[CH3:16].[OH-].[Na+].C(OCC)(=O)C>CS(O)(=O)=O.CO>[CH2:15]([C:17]1[CH:18]=[C:19]2[C:20](=[CH:21][CH:22]=1)[NH:23][CH2:24][CH2:25][C:26]2=[O:28])[CH3:16]
Reactant: CCOC(=O)CCNc1ccc(CC)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1ccc2c(c1)C(=O)CCN2
Temperature: 130 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A solution of phosphorus pentoxide (19.53 g) in methane sulfonic acid (200 mL) was heated to 130° C. The mixture was stirred at 130° C. for one hour until all the phosphorus pentoxide had dissolved. The mixuture was allowed to cool for 15 minutes and ethyl N-(4-ethylphenyl)-beta-alaninate (19.53 g of mono and di-ester mixture) was added. The mixture was heated to 130° C. for one hour and allowed to slowly cool overnight. The mixture was then cooled in an ice bath and 10N sodium hydroxide was added until the pH reached 9.5. Ethyl acetate was added to the mixture to help dissolve solids. The remaining gummy dark solids were dissolved in methanol and added to the ethyl acetate-aq. sodium hydroxide mixture. Semi-crystalline solids precipitated and were removed by filtration through Celite. The filtrate was washed with water, followed by 1N sodium hydroxide and brine, dried with magnesium sulfate, filtered, and concentrated. Silica gel chromatography using 0.25% ammonium hydroxide in dichloromethane gave mixed fractions. The mixed fractions were combined and re-chromatographed using 30% ethyl acetate in heptane. The resulting material was further upgraded by formation of the hydrochloride salt using 2N HCl in ether. The salt was collected by filtration and washed with heptane and dried in an oven under vacuum at 50° C. overnight. The salt was then partitioned between dichloromethane and 1N sodium hydroxide. The organic layer was extracted twice with dichloromethane, washed with 1N sodium hydroxide, dried with sodium sulfate, filtered, and concentrated to give 3.83 g of the title compound. MS (ESI+) for C11H13NO m/z 175.96 (M+H)+.
Reaction SMILES: Cl[C:2]1C(CCC)[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18].C(Cl)Cl.N(Cl)Cl>C(O)C.O>[NH:17]([C:2]1[N:3]([CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:18]
Reactant: CCCC1C(=O)c2ccccc2N=C1Cl
Reactant: NN
Agent: ClNCl
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCCn1c(NN)nc2ccccc2c1=O
Yield: 82 %

Procedure:
The crude solid imino chloride of Step C was dissolved in 800 ml of ethanol and 400 ml of hydrazine hydrate and the mixture was refluxed for two hours until TLC indicated (SiO2, CH2Cl2 /2% MeOH) that no imino chloride remained. 500 ml of water were added to the mixture and the mixture was cooled inducing a crystalline precipitate of the product. The precipitation was filtered, washed well with water, then dried over P2O5 under vacuum to obtain 158 g (82% yield) of 2-hydrazino-3-n-propylquinazolin-4(3H)-one in the form of a pale yellow solid melting at 125°-8° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CCN(C(C)C)C(C)C.[Cl:22][C:23]1[S:24][C:25]([Cl:31])=[CH:26][C:27]=1[C:28](O)=[O:29].O=P(Cl)(Cl)Cl.NCCNCCN.CCN(C(C1C=CC=C(C)C=1)=O)CC.[OH-]>ClCCCl.CC(N(C)C)=O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:28]([C:27]2[CH:26]=[C:25]([Cl:31])[S:24][C:23]=2[Cl:22])=[O:29])[CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: O=C(O)c1cc(Cl)sc1Cl
Agent: CCN(CC)C(=O)c1cccc(C)c1
Agent: NCCNCCN
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: O=C(O)c1ccc(Cl)cc1NC(=O)c1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). 2,5-Dichlorothiophene-3-carboxylic acid (23.6 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA, Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of 1M aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/0.1% formic acid, 30%-100% eluant gradient) to yield the final product (3.2 mg, 98% purity). MS (EI) for C12H6Cl3NO3S: 351 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:51]2[CH:59]=[C:57]([CH3:58])[C:55](=[O:56])[NH:54][C:52]2=[O:53])[C@@H:10]1[OH:60])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(=O)([O-])O.[Na+].ClCCl>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:10]2[O:60][CH2:39][C@:13]1([CH2:14][O:15][C:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[O:12][C@H:11]2[N:51]1[CH:59]=[C:57]([CH3:58])[C:55](=[O:56])[NH:54][C:52]1=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cc(C)c(=O)[nH]c4=O)O2)[C@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 95.4 %

Procedure:
To a solution of nucleoside 7 (4.22 g, 5.06 mmol) in anhydrous DMF (25 cm3) at 0° C. was added a 60% suspension of sodium hydride in mineral oil (w/w, 0.607 g, 1 5.7 mmol, added in four portions during 20 min) and the reaction mixture was stirred at room temperature for 25 h, cooled to 0° C. and diluted with dichloromethane/pyridine (100 cm3, 99.5:0.5, v/v). A saturated aqueous solution of sodium hydrogen carbonate (120 cm3) was added whereupon extraction was performed using dichloromethane (75 cm3×2). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (60 cm3×3) and brine (40 cm3×3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5–1.5% methanol; 0.5% pyridine, v/v/v) as eluent yielding nucleoside 8 (3.2 g, 96%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[C:3]1=[O:26].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[C:3]1=[O:26]
Reactant: Cc1ccc(C2CN(C)C(=O)C23CCCN(C(=O)OC(C)(C)C)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2CN(C)C(=O)C23CCCNC3)cc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a stirred solution of tert-butyl 2-methyl-1-oxo-4-p-tolyl-2,7-diazaspiro[4.5]decane-7-carboxylate (270 mg, 0.753 mmol) in DCM (5 ml) at 5° C. was added TFA (870 ul, 11.30 mmol) and the reaction mixture was left to stir at 5-10° C. for 1 hr. The reaction mixture was added to 2M NaOH (5 ml) and extracted with DCM (3×5 ml). The organics were combined, washed with brine (5 ml), dried (MgSO4) and concentrated to give the crude product as a white solid (176 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][OH:8].FC(F)(F)C(O)=O.N1([C:21]([O:23][CH:24]([N:28]2[N:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:30]([C:38](=[O:52])[C:39]3[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:40]=3[N+:49]([O-:51])=[O:50])=[N:29]2)[CH:25]([CH3:27])[CH3:26])=[O:22])C=CN=C1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:21]([O:23][CH:24]([N:28]1[N:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:30]([C:38](=[O:52])[C:39]2[CH:44]=[C:43]([O:45][CH3:46])[C:42]([O:47][CH3:48])=[CH:41][C:40]=2[N+:49]([O-:51])=[O:50])=[N:29]1)[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: CCOC(=O)c1nn(C(OC(=O)n2ccnc2)C(C)C)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Reactant: COCCOCCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nn(C(OC(=O)OCCOCCOC)C(C)C)nc1C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
In the same manner as in Example 19 (19b), provided that diethylene glycol monomethyl ether (3.6 ml) was used instead of 3-pentanol and trifluoroacetic acid (3.8 ml) was added, ethyl 2-(1-(2-(2-methoxyethoxy) ethoxycarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (8.82 g, 52%) was prepared from ethyl 2-(1-(1-imidazolylcarbonyloxy)-2-methylpropyl)-5-(4,5-dimethoxy-2-nitrobenzoyl)-2H-1,2,3-triazole-4-carboxylate (13.0 g) prepared in step (30a).