Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]2[C:7]([O:9][C:10](=[O:11])[C:3]1=2)=[O:8].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[C:3]=2[C:10]([OH:9])=[O:11])=[O:8])=[CH:15][CH:14]=1
Reactant: Cn1ccc2c1C(=O)OC2=O
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cn1ccc(C(=O)c2ccc(F)cc2)c1C(=O)O

Procedure:
1-Methyl-2,3-pyrroledicarboxylic anhydride and fluorobenzene were subjected to substantially the same reaction and process as in Reference Example 1 Process 1 in the presence of aluminum chloride to give 3-(4-fluorobenzoyl)-1-methyl-2-pyrrolecarboxylic acid as colorless crystals.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33][C@H:34]([C:50]([O:52][CH3:53])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CNC.[NH:74]([C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])[C@H:75]([C:91](O)=[O:92])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][CH2:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)=[O:82].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.C(Cl)(Cl)Cl.CO>[NH:74]([C:94]([O:96][C:97]([CH3:100])([CH3:99])[CH3:98])=[O:95])[C@H:75]([C:91]([NH:1][C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:33][C@H:34]([C:50]([O:52][CH3:53])=[O:51])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])=[O:92])[CH2:76][CH2:77][CH2:78][CH2:79][NH:80][C:81]([O:83][CH2:84][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=1)=[O:82]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 14 (1.48 g, 1.52 mmol) in THF (30 mL), was added dimethyl amine (15.2 mL, 2M in THF, 30.4 mmol) at 0° C. This reaction was allowed to reach room temperature and stirred for 2 h. At this time, the reaction mixture was concentrated in vacuo. To the yellowish solid was added DCM (30 mL) and DMF (5 mL). To this solution, was added Boc-Lys(Z)—OH (0.608 g, 1.60 mmol), then HOBt (0.216 g, 1.60 mmol), then EDC.HCl (0.3063 g, 1.60 mmol). This solution was allowed to stir for 8 h at which time the organic solution was washed with 1N HCl (3×15 mL), then saturated NaHCO3 (3×15 mL), and finally H2O (3×15 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to yield a white solid. Column chromatography (2% MeOH, CHCl3) afforded the product 15 (1.0 g, 59% yield): 1H NMR (500 MHz, CDCl3) δ 8.15 (br s, 1H), 8.03 (br s, 1H), 7.88 (br s, 1H), 7.45-7.28 (m, 10H), 7.12 (br s, 1H), 6.65 (br s, 1H), 5.08 (s, 1H), 4.45-4.35 (m, 3H), 4.05 (br s, 1H), 3.67 (s, 3H), 3.11 (br s, 1H), 3.01 (br s, 1H), 1.90-1.60 (m, 8H), 1.60-1.38 (m, 44); 13C NMR (125 MHz, CDCl3) δ 173.3, 173.2, 172.7, 172.3, 157.2, 156.6, 138.4, 129.0, 128.4, 79.0, 78.1, 66.0, 55.7, 53.8, 53.4, 53.0, 52.2, 41.1, 40.9, 40.8, 32.7, 32.5, 31.6, 29.8, 29.6, 28.6, 23.7, 23.5; ESMS (FAB) m/z calcd for C66H88N8O15 (M+H)+ 1113.65, found 1113.52.
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([OH:19])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O>O>[CH:1]([S:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
A suspension of 16.45 g (0.06 mol) of (-)-benzhydrylsulfinylacetic acid in 300 ml of water is treated at 20° C. with 16.8 g (0.2 mol) of sodium bicarbonate and 18.8 ml (0.21 mol) of methyls sulfate, with stirring, the mixture is stirred for 16 to 18 hours at 20° C. and filtered and the material on the filter is washed with water and dried to give methyl (-)-benzhydrylsulfinylacetate with a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[C:14]=3[F:21])[N:11]=[N:10][N:9]=2)=[CH:6][C:5]([Br:22])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:46][CH2:45][C@H:44](O)[CH2:43]1>C1COCC1>[O:42]1[CH2:46][CH2:45][C@@H:44]([O:19][C:16]2[CH:17]=[CH:18][C:13]([N:12]3[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:22])[CH:6]=4)=[N:9][N:10]=[N:11]3)=[C:14]([F:21])[C:15]=2[F:20])[CH2:43]1
Reactant: O[C@H]1CCOC1
Reactant: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O)c(F)c1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1-c1nnnn1-c1ccc(O[C@@H]2CCOC2)c(F)c1F
Yield: 92.5 %

Procedure:
A solution of Compound 1086 (90 mg, 0.2438 mmol), triphenylphosphine (76.74 mg, 0.2926 mmol), diisoproplylazodicarboxylate (59.17 mg, 56.68 μL, 0.2926 mmol), and (S)-tetrahydrofuran-3-ol (25.78 mg, 0.2926 mmol) in THF (90 μL) was heated at 70° C. for 10 minutes under microwave irradiation. The reaction was quenched with ammonium chloride (satd') and extracted with EtOAc. The organics were washed with 1 M NaOH (2×), brine, dried over sodium sulfate, and concentrated under vacuum. The residue was chromatographed over silica gel (0-50% EtOAc/hexanes gradient) to give 3-(1-(4-((R)-tetrahydrofuran-3-yloxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-bromopyridin-2-amine (Compound 1090, 99 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1.CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>ClCCCl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:22])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OCCCl)cc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250-ml flask are combined 4-(2-chloroethoxy)benzoic acid (2.58 g, 12.9 mmol), dimethylformamide (0.2 ml) and 1,2-dichloroethane (50 ml). Oxalyl chloride (1.35 ml) is added dropwise and the reaction mixture stirred overnight at room temperature. The reaction becomes homogeneous after stirring several hours. After an overnight stir, the solvent is evaporated to dryness, and the solid product is redissolved in 1,2-dichloroethane (2×50 mL) and evaporated. The product is used as is in subsequent reactions.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[C:10]3[CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=[CH:17][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:21]=1.C1C2C=CC3C=CC=CC=3S(=O)(=O)C=2C=C(C(O)=O)C=1>>[OH:19][CH2:18][C:15]1[CH:16]=[CH:17][C:9]2[CH2:8][CH2:7][C:6]3[CH:21]=[C:2]([SH:1])[CH:3]=[CH:4][C:5]=3[S:11](=[O:13])(=[O:12])[C:10]=2[CH:14]=1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccc(S)cc1CC2
Agent: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Product: O=S1(=O)c2ccc(S)cc2CCc2ccc(CO)cc21

Procedure:
Repeat the process of Example 6, substituting an equivalent quantity of 8-mercapto-10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide for the dibenzo[b,f]thiepin-3-carboxylic acid 5,5-dioxide, to obtain the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])=O.[NH4+].[CH3:30][N+:31]([O-:33])=[O:32]>CC(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=[CH:30][N+:31]([O-:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 23 °C
Yield: 24.1 %

Procedure:
A mixture of 79.5 g (1.25 mol) of 3,4-dibenzyloxybenzaldehyde (11) (available from Aldrich Chemical Co.), 47 g CH3CO2NH4, 47 g CH3NO2, and 400 ml CH3CO2H is refluxed for two hours. The mixture is cooled to 23° C. to precipitate the product. The yellow solid is isolated by filtration, washed with ethanol, and air dried. Recrystallization from CH3CO2H--C2H5OH gives 67.2 g (74.5%) of (12): mp 118°-119° C.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][CH:12]([Cl:14])[CH3:13])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[C:9](=[O:10])([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: Sc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
A solution of benzenethiol (50 g, 450 mmol) and 1-chloroethyl chloroformate (65 g, 450 mmol) in CH2Cl2 (300 mL) was cooled to 0-4° C. in an ice-water bath. To the mixture was added a solution of triethylamine (450 mmol) in dichloromethane (200 mL) dropwise over 30 min. The reaction was removed from the ice bath and stirred at ambient temperature for 12 h. The reaction was washed with water (3×500 mL), the organic phase was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the product as a pale yellow liquid (96 g, 98.5%). 1H NMR (CDCl3, 400 MHz): δ 1.82 (d, 3H), 6.6 (q, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9](=O)[CH:8]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9](=[S:33])[CH:8]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1c2ncccc2NC(=O)C1c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)OC(=O)N1c2ncccc2NC(=S)C1c1ccccc1
Yield: 62 %

Procedure:
200 mg (0.64 mmol) of 4-isopropoxycarbonyl-3-(R,S)-phenyl-3,4-dihydro-1,4,5-triazanaphthalen-2(1H)-one were reacted with 400 mg of Lawesson's reagent in analogy to Example 20 (reaction conditions: 10 hours at 80° C. The crude product was concentrated and chromatographed on silica gel (ethyl acetate/n-heptane=1:2). 130 mg (62%) of 4-isopropoxycarbonyl-3-(R,S)-phenyl-3,4-dihydro-1,4,5-triazanaphthalene-2(1H)-thione, of melting point 188°-189° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[O:27]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:25][C:26](=[O:27])[C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1ccncc1

Procedure:
1 g (3.94 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 3.85 g (11.83 mmol) of cesium carbonate, 1.33 g (4.73 mmol) of 2-bromo-1-pyrid-4-ylethanone hydrobromide and 100 mL of acetonitrile were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 60% B, t 25 min 100% B, t 30 min 100% B), 804 mg of (8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[CH3:99][NH:100][CH2:101][CH2:102][O:103][CH2:104][CH2:105][OH:106]>>[OH:106][CH2:105][CH2:104][O:103][CH2:102][CH2:101][N:100]([CH3:99])[C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1
Reactant: CNCCOCCO
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CN(CCOCCO)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. 2-(2-(Methylamino)-ethoxy)ethanol was used as the amine component in this coupling. 1H-NMR: (300 MHz, DMSO-d6+D2O, ppm): δ 9.58 (s, 1H), 8.91 (d, J=5.1 Hz, 1H), 8.46 (d, J=9 Hz, 1H), 8.36 (s, 1H), 7.87-7.96 (m, 4H), 7.545-7.689 (m, 7H), 4.61 (s, 2H), 3.29-3.49 (m, 12H), 2.97 (d, J=21.9 Hz, 3H), 1.84 (s, 4H), 1.68 (s, 2H). MS (ES, m/z): 704 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Mg+2]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][S:39]([C:40]5[N:44]([CH3:45])[CH:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4nncn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Mg+2]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4nncn4C)cc2)CCN3CC(C)C)cc1
Temperature: -12.5 °C
Reaction time: 1.5 h
Yield: 27.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26 g) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.26 g) in dichloromethane (10 ml) at −78° C. and the mixture was stirred at −10 to −15° C. for 1.5 hours. To the reaction solution was added magnesium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylsulfinylmethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 118) (73.8 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:7][CH2:6][CH:5]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.O1CCCC1.[OH-].[Li+]>O>[CH3:1][C:2]1([C:12]([OH:14])=[O:13])[CH2:7][CH2:6][CH:5]([O:8][CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)OC1CCC(C)(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC1CCC(C)(C(=O)O)CC1
Yield: 71.2 %

Procedure:
Phenylmethyl 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylate (D108) (2.3 g, 7.92 mmol) was suspended in water (30 mL) and tetrahydrofuran (THF) (10 mL) along with lithium hydroxide (0.759 g, 31.7 mmol). The resulting solution was warmed to reflux overnight, TLC (SiO2 10% EtOAc/is-hex) showed some of more polar SM present but none of less polar SM. Reaction cooled and extracted with ether (2×20 mL) to remove unhydrolysed SM. Aqueous layer acidified with 2 N HCl (acid to pH stick) and extracted into DCM (2×15 mL). DCM layers combined and dried over MgSO4, filtered and solvent removed under reduced pressure. NMR confirmed 1-methyl-4-[(1-methylethyl)oxy]cyclohexanecarboxylic acid (1.13 g, 5.64 mmol, 71.2% yield) as a mixture of cis and trans isomers. As suspected from the TLC one of the isomers, suspected to be the trans (ether:carboxylate) had hydrolysed faster. This resulted in a ˜2:1 ratio of the acids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH2:7][CH2:6]2.CO.[BH4-].[Na+]>C1COCC1.Cl[Ni]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH2:7][CH2:6]2
Reactant: COCC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(=O)N1CCc2cc(OC)c(N)cc21
Yield: 25.2 %

Procedure:
A slurry of 5-(methyloxy)-1-[(methyloxy)acetyl]-6-nitro-2,3-dihydro-1H-indole (3.96 g, 14.87 mmol) and NiCl2 6H2O (1.061 g, 4.46 mmol) in THF (50 mL) and MeOH (100 mL) was treated with NaBH4 (1.69 g, 44.6 mmol) in small portions. After 5 minutes the reaction mixture was concentrated onto Celite and purified by silica gel chromatography using THF. The crude product was triturated using CH2Cl2 and Et2O to obtain 5-(methyloxy)-1-[(methyloxy)acetyl]-2,3-dihydro-1H-indol-6-amine as a white solid (884 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98 (t, J=8.24 Hz, 2H), 3.34 (s, 3H), 3.71 (s, 3H), 3.93 (t, J=8.,33 Hz 2H), 4.12 (s, 2H), 4.67 s, 2H), 6.71 (s, 1H), 7.54 (s, 1H); ESIMS (M+H)+=237.4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)ncn1
Temperature: 90 °C
Yield: 104.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 6-methylpyrimidin-4-amine (800 mg, 2.6 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (694 mg, 2.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (238 mg, 0.26 mmol), XantPhos (300 mg, 0.52 mmol), Cs2CO3 (1.7 g, 5.2 mmol), and 1,4-dioxane (30 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2.5 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 180a as a yellow solid (800 mg, 36%). MS-ESI: [M+H]+ 295.1
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>ClCCl.CN(C=O)C>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([CH2:12][CH2:11][N:10]3[S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:14][CH:15]=2)=[O:20])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccccc2)CC3)cc1
Reaction time: 2 h

Procedure:
Benzenesulfonyl-2,3-dihydro-1H-indole-6-carboxylic acid (40 mg, 0.13 mmol) was added to a solution of thionyl chloride (63 mg, 0.53 mmol, 4 equiv.) in dichloromethane (5 ml) and DMF (1 ml). The reaction mixture was stirred for 2 hours, then the solvent was removed. The crude acyl chloride was redissolved in dichloromethane (5 ml) and treated with 4-amino benzoic acid methyl ester (80 mg, 0.53 mmol, 4 equiv.). The mixture was stirred for 30 min. at room temperature, then the solvent was removed. The residue was purified by flash chromatography, yielding 4-[(1-benzenesulfonyl-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester as a white solid, 42 mg (73%). MS (ISP): m/e=437.3 (M+H+.), δH (300 MHz; CDCl3) 8.02-8.09 (4H, m), 7.82 (2H, d), 7.77 (2H, d), 7.45-7.61 (4H, m), 7.21 (2H, d), 3.98 (2H, t), 3.92 (3H, s), 2.97 (2H, t).
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][O:22]C(=O)C)[C@@H:15]([O:16]C(=O)C)[C@H:10]1[O:11]C(=O)C.O[Li].O.C(Cl)(Cl)Cl.CO>O1CCOCC1.O>[F:1][C:2]1[N:3]=[C:4]([NH2:29])[C:5]2[N:6]=[CH:7][N:8]([C:27]=2[N:28]=1)[C@@H:9]1[O:26][C@H:20]([CH2:21][OH:22])[C@@H:15]([OH:16])[C@H:10]1[OH:11]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)nc(F)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoro-2',3',5'-tri-O-acetyladenosine (0.41 g, 1.0 mmol, lt. yellow solid) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL) . The solution was stirred at ambient temperature and solid LiOH·H2O (1.40 mL, 3.5 mmol) was added in one portion. The progress of the reaction was monitored by TLC (9:1 Chloroform:methanol). After 2 hours, most of the suspended solid had dissolved and TLC showed no acetylated intermediates remaining. The cloudy reaction mixture was poured directly onto a column of AG 50-X4 (H+, 100-200 mesh, 10 mL bed volume) ion exchange resin and the column was eluted with several column volumes of 1:1 methanol:water. 2-Fluoro-adenosine began to elute immediately, and all fractions which contained 2-fluoroadenosine were concentrated under vacuum to obtain a white partially crystalline solid which was dried overnight at 60° C. under vacuum: 0.18 g (63% yield), mp 227°-230° C. (d). This material was consistent by TLC, IR and UV with an authentic sample of 2-fluoroadenosine.