Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].C(Cl)Cl.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](O)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CO>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNCC[C@H](O)c1cccs1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%); 1H-NMR (DMSO-d6, 400 MHz): 8.1 (1H, s, broad), 7.5 (2H, dm), 7.42 (1H, dd), 7.1 (2H, dm), 7.0 (2H, m), 4.92 (1H, dd), 2.97 (2H, m, symm.), 2.57 (3H, s), 2.28 (3H, s), 2.0 (2H, m); 13C-NMR (DMSO-d6, 100 MHz): 149.3, 145.5, 137.6, 128.0, 126.6, 125.4, 124.4, 123.0, 66.1, 45.8, 35.1, 32.7, 20.7.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH2:2][CH2:3][CH3:4].CO[C:15]1[C:16](=O)[CH:17]=[C:18](OC)[C:19](=O)[CH:20]=1>C(O)(=O)C>[CH2:1]([N:5]1[C:18]2[C:19]([CH:20]=[C:15]3[C:16]([CH:17]=2)=[N:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[N:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: COC1=CC(=O)C(OC)=CC1=O
Reactant: CCCCNc1ccccc1N
Solvent: CC(=O)O
Product: CCCCN1c2ccccc2N=c2cc3c(cc21)=Nc1ccccc1N3CCCC
Yield: 98.4 %

Procedure:
1.65 g (10 mmol) N-butyl-2-aminoaniline and 0.84 g (5 mmol) 2,5-dimethoxybenzoquinone i 50 ml glacial acetic acid are heated to boiling under reflux for three hours followed by evaporation to dryness. The darkblue powder is treated with 50 ml 10% ammonia solution and washed thoroughly with water, ethanol, and acetone (10 ml). After a thorough drying under vacuum, 1.95 g (95%) 5,12-dibutyl-5,12-dihydro-5,7,12,14-tetraazapentacene is obtained.
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[C:8]([OH:31])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1.[C:33]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]3[O:31][CH2:33][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:20][C:21]5[O:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=5)[C:12]4=[O:30])[C:9]3=[CH:10][C:4]=2[O:3]1
Reactant: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1cc3c(cc12)OC(F)(F)O3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 2,2-difluoro-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (55%) as an off-white solid: mp 59-60° C. (recrystallized from the melt); 1H NMR (300 MHz, CDCl3) δ7.37-7.30 (m, 1H), 7.21-7.15 (m, 1H), 7.14-7.07 (m, 1H), 7.02 (d, J=7.9 Hz, 1H), 6.79-6.74 (m, 1H), 6.72 (s, 1H), 6.44-6.40 (m, 1H), 6.36 (s, 1H), 5.12-4.83 (m, 3H), 4.73 (d, J=9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.7, 157.0, 151.8, 144.7, 142.2, 141.7, 141.5, 138.5, 135.4, 132.0, 131.4, 129.6, 128.6, 124.2, 122.4, 120.7, 117.1, 112.8, 109.6, 109.3, 104.6, 94.4, 80.6, 58.0, 37.1; MS (ES+) m/z 465.7 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[CH3:12][O-].[Na+].[Cl-]>CO.CN(C=O)C>[CH3:12][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: Oc1cccc2cnccc12
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc2cnccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-hydroxyisoquinoline (10 g, 69 mmol) in MeOH (100 ml) was added a solution of sodium methoxide in methanol (30% by weight, 13.8 ml, 72.4 mmol) followed by phenyltrimethylanmmonium chloride (12.4 g, 72.4 mmol). The reaction mixture was stirred at room temperature for 2 h, after which time it was filtered and the filtrate evaporated under reduced pressure to afford an oil which was dissolved in DMF (50 ml). The reaction mixture was refluxed for 2 h after which time the reaction mixture was evaporated under reduced pressure. The resulting oil was partitioned between CH2Cl2 and 1N aqueous NaOH, the organic layer was washed twice with 1N aqueous NaOH, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified on silica gel eluting with EtOAc/hexane (1/1, v/v) to afford the subtitle compound as a yellow oil (6.11 g, 56%). 1H NMR (CDCl3) δ: 4.05 (3H, s), 7.00 (1H, d), 7.55 (2H, m), 8.02 (1H, d), 8.55 (1H, d), 9.22 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[C:24]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([N:35]2[CH2:36][CH2:37][N:32]([C:24]3[C:25]([CH3:31])=[C:26]([CH3:30])[CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:33][CH2:34]2)=[O:21])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Product: CCc1cc(NC(=O)N2CCN(c3c(C)c(C)cc(C)c3C)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1.[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH:15]([NH:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:17]
Reactant: CC(=O)OC(C)=O
Reactant: CON=C(C(=O)O)c1nc(N)sc1C
Solvent: O=CO
Product: CON=C(C(=O)O)c1nc(NC=O)sc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(2-amino-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.), acetic anhydride (31 ml.) and formic acid (13 ml.) was stirred at room temperature for 2 hrs. and then evaporated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then filtered. The filtrate was evaporated in vacuo. The oily residue was treated with n-hexane and diisopropyl ether, and the precipitates were collected by filtration to give 2-(2-formamido-5-methylthiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.8 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[C:30]([CH3:35])=[CH:31][C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][N:14](OC(C)(C)C)[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2].Cl>O1CCOCC1>[ClH:34].[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[C:30]([CH3:35])=[CH:31][C:32]([Cl:34])=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:36])[CH2:15][NH:14][CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CN(OC(C)(C)C)C1)C2c1ccc(Sc2nc3cc(Cl)cc(C)c3[nH]2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CNC1)C2c1ccc(Sc2nc3cc(Cl)cc(C)c3[nH]2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 196.6 %

Procedure:
290 mg of 6-tert-butyloxy-9-[5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-2,4,5,7,8,9-hexahydro-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester (example 137) are dissolved in 10 ml of dioxane and combined with 1.912 ml of 4N HCl in dioxane. The reaction mixture is stirred for 16 hours at room temperature. The formed insoluble material is collected by filtration, washed with dioxane (10 ml), diisopropylether (10 ml) and pentane (10 ml) and dried under vacuum to yield 268 mg of 9-[5-(5-chloro-7-methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]-1,7-naphthyridine-3-carboxylic acid ethyl ester hydrochloride. Yield=93%. Analytical LC/MS (method B): m/z=524 (positive ion mode [M+H]+, 1 Cl present), m/z=522 (negative ion mode [M−H]−, 1 Cl present).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[S:35]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36]1.Cl[C:44]1[N:49]=[CH:48][CH:47]=[CH:46][N:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(CC)(C)C>[S:35]1[CH:39]=[CH:38][C:37]([C:44]2[N:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[CH:36]1
Reactant: OB(O)c1ccsc1
Reactant: Clc1ncccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: c1cnc(-c2ccsc2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tert-amyl alcohol (100 mL) was added to tris(dibenzylideneacetone)dipalladium(0) (460 mg), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl (960 mg), 3-thiophene boronic acid (9.60 g), 2-chloropyrimidine (5.72 g), potassium phosphate (21.2 g), and molecular sieve 4 A (12.5 g). The reaction solution was stirred at 100° C. overnight. The insolubles were filtrated, and then the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 2-(thiophen-3-yl) pyrimidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:30])([F:31])[F:29])[C:9]=3[CH:17]=2)[CH:19]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(NCc1ccccc1Cl)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.9 (M+H+); retention time=0.98 minutes.
Reaction SMILES: Br[C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.BrC1C(F)=CC(F)=C(C=1)C=O.F[C:39]1[CH:44]=[CH:43][C:42]([N+]([O-])=O)=[CH:41][C:40]=1[C@@:48]12OCC[C@@H]1CS[C:50](NC(=O)OC(C)(C)C)=[N:49]2.FC1C=CC([N+]([O-])=O)=CC=1C=O.BrC1C(F)=CC(F)=C([C@@]23OCC[C@@H]2CSC(NC(=O)OC(C)(C)C)=N3)C=1.C(C1C=C(B(O)O)C=NC=1)#CC.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.CCO.O.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>[F:25][C:5]1[CH:4]=[C:3]([F:26])[C:2]([C:40]2[CH:48]=[N:49][CH:50]=[C:42]([C:43]#[C:44][CH3:39])[CH:41]=2)=[CH:7][C:6]=1[C@:8]12[O:16][CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc([N+](=O)[O-])ccc3F)OCC[C@@H]2CS1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(Br)c(F)cc3F)OCC[C@H]2CS1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC#Cc1cncc(B(O)O)c1
Agent: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(Br)c(F)cc3F)OCC[C@@H]2CS1
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC#Cc1cncc(-c2cc([C@@]34N=C(NC(=O)OC(C)(C)C)SC[C@@H]3CCO4)c(F)cc2F)c1
Temperature: 100 °C

Procedure:
(±)-tert-butyl (4aR,7aR)-7a-(5-bromo-2,4-difluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate was made from 5-bromo-2,4-difluorobenzaldehyde in the same fashion as (±)-tert-butyl (4aS,7aS)-7a-(2-fluoro-5-nitrophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate from 2-fluoro-5-nitrobenzaldehyde (Step A to Step F, Preparation 1). A mixture of (±)-tert-butyl (4aS,7aS)-7a-(5-bromo-2,4-difluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (60 mg), 5-(prop-1-ynyl)pyridin-3-ylboronic acid (Preparation 9, 86 mg), cesium carbonate (174 mg), and PdCl2(PPh3)2 (19 mg) in DME (0.44 mL), EtOH (0.22 mL) and water (0.22 mL) was heated at 100° C. for 10 min in a microwave, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a white foam (22 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.65 (br. s., 1H), 7.82 (s, 1H), 7.65 (t, J=8.7 Hz, 1H), 7.00 (t, J=10.3 Hz, 1H), 4.23-4.13 (m, 1H), 4.12-4.04 (m, 1H), 3.30 (d, J=11.5 Hz, 1H), 3.00-2.83 (m, 2H), 2.47-2.35 (m, 1H), 2.28-2.16 (m, 1H), 2.14-2.10 (m, 3H), 1.50 (s, 9H). MS (M+H)+: 486.3.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.[C-]#N.[Na+].[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2]1[N:3]=[N:4][C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:17]
Reactant: Clc1ccc2nc(Cl)nnc2c1
Reactant: CCO
Agent: [C-]#N
Agent: [Na+]
Product: CCOc1nnc2cc(Cl)ccc2n1

Procedure:
A suspension of 20.2 g (0.1 mole) of 3,7-dichlorobenzo-1,2,4-triazine and 12.2 g (0.25 mole) of sodium cyanide in 200 ml of ethanol was boiled under reflux for 2 hours. The salts were filtered off and the filtrate was evaporated in vacuo. The residue was stirred with water and cooled in ice for some time. The crystallized mass was filtered off and recrystallized from wash benzine. 17.6 g, that is to say 84% of theory, of 3-ethoxy-7-chloro-benzo-1,2,4-triazine with a melting point of 90°-92° C were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH3:18])=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([NH2:16])=[O:15])=O)[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH3:17])[N:11]=[C:10]([CH3:18])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C)nn(C)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccccc1-c1nc2c(C)nn(C)c2c(=O)[nH]1
Temperature: 140 °C

Procedure:
4-(2-Ethoxybenzamido)-1,3-dimethylpyrazole-5-carboxamide (1.6 g, 5.29 mmol) was added to polyphosphoric acid (50 g) and the mixture heated to 140° C. for 6 hours. The solution was cooled, poured into ice-water (100 ml), and then the mixture was basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (3×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. The residue was chromatographed on silica gel eluting with a 97:3 mixture of dichloromethane and methanol. Crystallisation of the crude product from aqueous ethanol gave the title compound as a colourless solid, m.p. 201°-204° C. Found: C,63.43; H,5.57; N,19.35. C15H16N4O2 requires C,63.36; H,5.67; N,19.71%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+]>C(O)(=O)C.O>[C:16]([O:19][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1CCl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 60 h
Yield: 97.9 %

Procedure:
2 g (8.348 mmol) of 1-chloromethyl-2-nitro-4-trifluoromethylbenzene are added, at a temperature in the region of 20° C., under an argon atmosphere, to 20 g (244 mmol) of sodium acetate in solution in 100 cm3 of acetic acid. After stirring for 60 hours at a temperature in the region of 100° C., the reaction mixture is diluted with 200 cm3 of water and then extracted with 2 times 300 cm3 of dichloromethane. The organic phases are combined, washed with 100 cm3 of water, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure (2.7 kPa), to give 2.15 g of 2-nitro-4-trifluoromethylbenzyl acetate in the form of an orange oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][O:24][C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:35])([CH3:34])[C:19](=[O:33])[NH:20]2)=[CH:15][CH:14]=1.CI.[C:38](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]([CH2:23][O:24][C:25]([C:27]2[S:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:26])=[C:21]2[C:16]([NH:17][C:18]([CH3:35])([CH3:34])[C:19](=[O:33])[N:20]2[CH3:38])=[CH:15][CH:14]=1
Reactant: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)NC(=O)C(C)(C)N3)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)s2)N(C)C(=O)C(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A mixture of 7-(2-methoxy-4-methoxymethoxyphenyl)-8-(5-methylthiophen-2-ylcarbonyloxymethyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 11, 1.58 g, 3.18 mmol), methyl iodide (400 μL, 6.43 mmol), and cesium carbonate (2.24 g, 6.87 mmol) was suspended in anhydrous N,N-dimethylformamide (30 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL), washed with water (150 mL) and saturated brine (150 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.38 g) as a pale yellow amorphous product. (Yield 85%)
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:33]([C:30]4([CH3:29])[CH2:32][CH2:31]4)=[O:34])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC1(C(=O)O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C2(C)CC2)C3)cc1

Procedure:
Compound fd was prepared according to the procedure described in Example 213 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-methylcyclopropanecarboxylic acid. LC-MS: m/z=+465 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:4]([OH:13])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[NH2:2][C@@H:3]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C@@H:4]([O:13][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])[CH2:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: CCCCNC(=O)C[C@H](O)[C@@H](N)CC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)CC1CCCCC1
Yield: 78.5 %

Procedure:
A solution of the HCl salt of (3S,4S)-4-amino-N-butyl-5-cyclohexyl-3-hydroxypentanamide (279 mg, 1.03 mmol), TBSCl (311 mg, 2.06 mmol) and imidazole (281 mg, 4.12 mmol) in dry DMF (2 mL) was stirred at rt for 2 d. The mixture was diluted with EtOAc (90 mL), washed with 1:1 water/brine (3×20 mL), dried over Na2SO4 and concentrated to leave crude (3S,4S)-4-amino-N-butyl-3-(tertbutyldimethylsilyloxy)-5-cyclohexylpentanamide (311 mg, 78%) as a yellow syrup.
Reaction SMILES: [CH3:1][O:2][C:3](OC)(OC)[CH:4]([CH3:6])[CH3:5].[OH:11][C@H:12]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH3:13].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH:4]([C:3]1([O:2][CH3:1])[O:17][C@H:15]([CH3:16])[CH2:14][C@@H:12]([CH3:13])[O:11]1)([CH3:6])[CH3:5]
Reactant: COC(OC)(OC)C(C)C
Reactant: C[C@H](O)C[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC1(C(C)C)O[C@H](C)C[C@@H](C)O1
Yield: 79 %

Procedure:
A mixture of 15.6 g (0.105 mol) of 1,1,1-trimethoxyisobutane, 10 g (0.0962 mol) of 2(S),4(S)-dihydroxypentane, and 251 mg of PPTS in 150 ml of toluene (dried over 3° A sieves) was allowed to reflux under argon for 11/2 hours while azeotroping water formed using the Dean-Stark trap. The reaction mixture was cooled, 1.2 g of potassium tert. butoxide was added, and the solvent was distilled. Ether (100 ml) was added to the residue, passed through a supercel pad eluting with 300 ml of ether, and the combined solvent was distilled in vacuo (<40° C.). The residue was distilled to afford 14.3 g (79.4%) of 2-isopropyl-2-methoxy-4(R),6(R)-dimethyl-1,3-dioxane, b.p. 78°-82° C./15 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(F)cc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-fluoro-5-methoxybenzoic acid (5 g, 0.029 mol) was stirred in CH2Cl2 (50 ml) at 0° C. under an argon atmosphere. DMF (9 drops, catalytic) was added, followed by oxalyl chloride (12.7 ml, 0.147 mol). Reaction was warmed to room temperature then stirred under argon for one hour. Reaction was concentrated in vacuo to yield 3-fluoro-5-methoxybenzoyl chloride (BA67).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:16][C@H:15]([OH:17])[C@@H:14]([CH2:18][OH:19])[O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:23]>P([O-])([O-])([O-])=O>[NH:3]1[C:4](=[O:23])[C:5]2[N:6]=[CH:7][N:8]([C@H:11]3[CH2:16][C@H:15]([OH:17])[C@@H:14]([CH2:18][OH:19])[O:13][CH2:12]3)[C:9]=2[N:10]=[C:2]1[NH2:1]
Reactant: Nc1nc(Cl)c2ncn([C@@H]3CO[C@H](CO)[C@@H](O)C3)c2n1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Product: Nc1nc2c(ncn2[C@@H]2CO[C@H](CO)[C@@H](O)C2)c(=O)[nH]1
Reaction time: 4 h

Procedure:
A mixture of 145 mg (0.48 mmol) of compound 12 and 0.5 ml of a suspension of adenosine deaminase in 100 ml 0.05 M phosphate buffer, pH 7.5, was incubated for 4 hours at 30° C. The reaction mixture was concentrated to about 15 ml and the precipitate filtered off. Recrystallization from water provided 50 mg analytically pure compound 13. The filtrates were placed onto an XAD column (25×2 cm), which was eluted with water followed by MeOH-water (3:1). Evaporation gave an extra 70 mg of compound 13 as a white product to a total of 0.43 mmol (89%). mp >300° C.