Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C(C(OO)=O)=CC=CC=1>[Br:15][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OO)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cccn1-c1ccc(CBr)cc1
Yield: 94 %

Procedure:
A solution of 1-(4-methylphenyl)pyrrole-2-carbonitrile (4.9 g), N-bromosuccinimide (5.5 g) and perbenzoic acid (65 mg) in carbon tetrachloride was heated under reflux in light radiation for 2 hours. After removal of insoluble materials by filtration, the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford a colorless syrup (6.6 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[O:14]>>[CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)=[O:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cccc2[nH]cnc12
Product: Cc1cccc2c1ncn2CC(=O)Nc1cccc(C(F)(F)F)c1
Yield: 39 %

Procedure:
The title compound was synthesized in 39% yield (65 mg) according to a procedure described in Example 92, using 4-methyl-1H-benzoimidazole (66 mg, 0.5 mmol) and 2-bromo-N-(3-trifluoromethyl-phenyl)-acetamide (Example 92, part A) (141 mg, 0.5 mmol). Calculated for C17H14F3N3O m/z: 333.11, found 334.07 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 5.18 (s, 2H), 7.01 (d, J=7.6 Hz, 1H), 7.12 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 8.18 (s, 1H), 10.77 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=O)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O1CCCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=3)[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(Cl)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H]3c4ccc(Cl)cc4CC[C@H]3[C@@H]1CC[C@@H]2NCc1cccc(C(F)(F)F)c1
Reaction time: 24 h
Yield: 67.1 %

Procedure:
The compound, 3-chloroestra-1,3,5(10)-trien-17-one (2.17 g) is added to a solution of 3-(trifluoromethyl)benzylamine (2.6 g) in methanol (200 ml) and tetrahydrofuran (200 ml) made acidic with acetic acid (1.5 ml). When the starting material is dissolved, sodium cyanoborohydride (0.72 g) is added, the mixture is stirred 24 hours, additional sodium cyanoborohydride (0.7 g) is and the mixture is stirred for another 21 hours. The mixture is diluted with water (200 ml), made basic with 50% sodium hydroxide and extracted with methylene chloride (3×100 ml). The combined extracts are washed with brine, dried over magnesium sulfate and the solvent is removed. The product is chromatographed on silica gel and recrystallized in methylene chloride/hexane to give the title compound (2.26 g).
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:64][O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:21][O:22][C:23](=[O:63])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH2:34][CH:33]1[CH:38]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[O:39][CH:40]([C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:84]1(=[O:90])[O:89][C:87](=[O:88])[CH2:86][CH2:85]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH:40]([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)[O:39][CH:38]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:33]2[N:32]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([O:22][CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:64][O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:63])[CH2:36][CH:35]([O:37][C:84](=[O:90])[CH2:85][CH2:86][C:87]([OH:89])=[O:88])[CH2:34]2)=[CH:46][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1)OCCCCCCCCCCCCCCCCCC
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(COC(=O)NCCCCCC(=O)N1CC(OC(=O)CCC(=O)O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1)OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
Referring to scheme 5, Compound 12 (5.6 g, 4.8 mmol) was mixed with succinic anhydride (0.727 g, 7.26 mmol) and DMAP (0.062 g, 0.5 mmol) and dried in a vacuum at 40° C. overnight. The mixture was dissolved in anhydrous dichloromethane (20 mL), triethylamine (1.52 g, 2 mL, 15 mmol) was added and the solution was stirred at room temperature under argon atmosphere for 16 h. It was then diluted with dichloromethane (50 mL) and washed with ice cold aqueous citric acid (5% wt., 50 mL) and water (2×50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography to afford compound 14 as white solid (2.85 g, 47% yield; Rf=0.65 in 10% MeOH/CHCl3).
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:13](OC1C=CC=C2C=1C=CN2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C=O.[OH-].[Na+]>CCO>[CH2:13]([O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]2[CH2:2][OH:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCn1ccc2c(O)cccc21
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCn1ccc2c(OCc3ccccc3)cccc21

Procedure:
1-Hydroxymethyl-4-hydroxy-indole: A solution of 4-benzyloxyindole (1.0 g, 4.48 mmol), formaldehyde (2.0 mL, 26.8 mmol) and 2 N NaOH (2.24 mL, 4.48 mmol) in 10 mL EtOH was stirred at the room temperature for 4 h. The solvent was removed in vacuo. The crude material was purified by flash column chromatography (3:1, hexane:ethyl acetate) to yield 1.13 g of 4-benzyloxy-1-hydroxymethylindole, which was hydrogenated by 5% Pd/C in 40 mL methanol under H2 (50 psi) to yield 580 mg (79.5%) of the title compound. 1H NMR (CDCl3): 7.15-7.07 (m, 3H), 6.60-6.55 (m, 2H), 5.62 (d, J=7.5 Hz, 2H), 4.93 (s, 1H), 2.37 (t, J=7.2 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15][CH2:14]1>CN(C)C=O>[Cl:8][C:9]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:10]=1[CH2:11][O:12][C@H:13]1[O:18][C@@H:17]([CH2:19][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:16][CH2:15][CH2:14]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@@H](OCc3ccc(Cl)cc3Cl)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CO[C@@H]2CCC[C@H](Cn3ccnc3)O2)c(Cl)c1
Yield: 69 %

Procedure:
As in Example 1(b), 16 mg of imidazole, 10 mg of 55% sodium hydride and 70 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran were reacted in dimethylformamide, to give 37 mg of the title compound in the form of a colourless oil.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:15])[N:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[Cl:16][C:17]([SH:20])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:16][C:17]1[S:20][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[N:15]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1CCN(C(=N)N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of ethyl 1-[amino(imino)methyl]piperidine-4-carboxylate hydrochloride (1.50 g, 6.36 mmol) and perchloromethyl mercaptan (1.37 ml, 12.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.04 g, 50.9 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.10 g (62.9%) of the desired product as an oil.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9].[S:22]1C=CC=C1S(N1C2C(=C(C=C)C=CC=2)C=C1)(=O)=O.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O>[S:22]1[CH:6]=[CH:7][CH:2]=[C:3]1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1

Procedure:
The experimental for Intermediate 16 was followed using 1-(2-thienylsulfonyl)-4-vinyl-1H-indole (333 mg, 1.15 mmol; Intermediate 21), OsO4 (15 mg, 0.06 mmol), 2,6-lutidine (268 μL, 2.30 mmol) and sodium periodate (0.984 g, 4.60 mmol). The title compound was obtained (306 mg, 91%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C13H9NO3S2 m/z 292 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2Cl)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:22]>O1CCCC1>[CH3:1][O:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:21]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:19]([Cl:18])[CH:20]=1)=[O:6]
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: COCNC(=O)c1ccc2ncnc(Cl)c2c1
Solvent: C1CCOC1
Product: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
4-Chloroquinazoline-6-carboxylic acid methoxymethylamide (XIV-1, 5.78 g) was dissolved in tetrahydrofuran (100 ml), and 5.39 g of 3-chloro-4 (pyridin-2-ylmethoxy)aniline was added, followed by stirring at 60° C. for 1 hour. A precipitate was filtered, and washed with tetrahydrofuran to obtain 4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-quinazoline-6-carboxylic acid methoxymethylamide (XI-2, 7.87 g) as a white solid. The filtrate was allowed to stand at room temperature, and the resulting precipitate was collected by filtration, to newly obtain 2.21 g of XI-2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[S:13][C:14]2[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:11][C:12]1[S:13][C:14]2[C:20]([CH:21]=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Cc1nc2cccc(CO)c2s1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc2cccc(C=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (3.78 mL, 44.6 mmol) in dichloromethane (20 mL) was added dimethyl sulfoxide (4.75 mL, 66.9 mmol) at −78° C. and the mixture was stirred for 30 min. To the reaction mixture was added (2-methyl-1,3-benzothiazol-7-yl)methanol (4.00 g, 22.3 mmol) at −78° C. and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (18.8 mL, 134 mmol) at −78° C. and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and the mixture was further stirred at room temperature for 4 hr. Saturated aqueous ammonium chloride solution was added and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by recrystallization (dichloromethane/hexane) to give the title compound (3.54 g, yield 90%).
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][N+:16]([O-:5])=[CH:15][C:14]=1[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(Cc1cnccc1Cl)C(=O)OC(C)(C)C
Solvent: CC#N
Product: CN(Cc1c[n+]([O-])ccc1Cl)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Phthalic anhydride (566 mg, 3.82 mmol) was dissolved in acetonitrile (10 mL) and treated with urea-hydrogen peroxide complex (360 mg, 3.82 mmol) and the suspension was stirred for 15 min. A portion of the Boc-derivative from stage (i) (890 mg, 3.48 mmol) was added and the suspension was stirred at room temperature for 20 h. The residue was partitioned between potassium carbonate solution (100 mL) and DCM (200 mL). The organic layer was separated and the aqueous layer was re-extracted with DCM (3×50 mL). The combined organic fractions were washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography [SiO2; DCM/MeOH/880 NH3 (90:10:1)] afforded the title compound (680 mg, 72%); δH (CDCl3, 300 MHz) 1.42 (9H, s), 2.91 (3H, s), 4.44 (2H, s), 7.23 (1H, d), 8.00 (1H, d), 8.08 (1H, s); MS m/z (TS+) 273 (MH+).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CC.[CH2:12](O)CCCCCCC(C)C>>[CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([CH3:8])[CH3:12]
Reactant: CCCCCCCCCCO
Reactant: CC(C)CCCCCCCO
Product: CC(C)CCCCCCO

Procedure:
n-decylalcohol, iso-decylalcohol
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1
Reactant: OCc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(CO)c3)c2o1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzofuran-2-carboxamide hydrochloride (Example 30A) and 65.3 mg (0.43 mmol) of 3-(hydroxymethyl)phenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.64 ml of 2 M sodium carbonate solution and 17.5 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 60° C. for 18 h. A further 17.5 mg (0.02 mmol) of PdCl2(dppf) are added and the mixture is stirred at 90° C. for a further 18 h. After cooling, the reaction mixture is filtered through kieselguhr. A first purification by preparative HPLC is followed by column chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 90:9:1). The product fractions are combined and concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 45 mg (24% of theory) of the title compound.
Reaction SMILES: ClC1N=C(N[C@H](C)CSC2SC3C=CC=CC=3N=2)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.BrC1N=C2C(N=CN2[C@@H]2O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)=C(Cl)N=1.C([O:66][C@@H:67]1[C@H:71]([O:72]C(=O)C)[C@@H:70]([CH2:76][O:77]C(=O)C)[O:69][C@H:68]1[N:81]1[C:103]2[N:102]=[C:101]([Br:104])[N:100]=[C:85]([NH:86][C@H:87]([CH3:99])[CH2:88][S:89][C:90]3[S:91][C:92]4[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=4[N:94]=3)[C:84]=2[N:83]=[CH:82]1)(=O)C.C[O-].[Na+]>CO>[S:91]1[C:92]2[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=2[N:94]=[C:90]1[S:89][CH2:88][C@H:87]([NH:86][C:85]1[C:84]2[N:83]=[CH:82][N:81]([C:103]=2[N:102]=[C:101]([Br:104])[N:100]=1)[C@@H:68]1[O:69][C@H:70]([CH2:76][OH:77])[C@@H:71]([OH:72])[C@H:67]1[OH:66])[CH3:99]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccccc5s4)nc(Br)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Br)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Br)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 14 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared as indicated in Example 5) (1.07 g, 3.6 mmol) with 2-bromo-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-9H-purine (see WO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666) (1.48 g, 3.0 mmol) followed by deacylation of the purified 2',3',5'-tri-O-acetyl-2-bromo-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine (0.20 g, 14%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.38 (3H, d, --CHCH3), 3.50-3.77 (4H, m, H-5'a, and H-5'b and --CH2 --), 3.94 (1H, d, H-4'), 4.12 (1 H, d, H-3'), 4.51 (1H, q, H-2'), 4.70 1H, m, --CHCH3), 5.05 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.36, 7.46 (2H, 2t, Ar-H), 7.86, 7.99 (2H, 2d, Ar-H), 8.40 (1H, s, H-8). HPLC retention time 6.74 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[O:6].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:21]=1)=[O:18]>>[CH3:14][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:29]2[CH2:30][CH2:31][CH:26]([C:22]3[N:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=3)[CH2:27][CH2:28]2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(C(=O)CCCCl)cc1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)n1
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)n3)CC2)cc1C

Procedure:
Prepared by Procedure G and Scheme AI using 4-chloro-1-(3,4-dimethylphenyl)-1-butanone and 2-methyl-N-[6-(4-piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 422.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([NH:27][C:28]([CH:30]1[NH:34][CH:33]2[CH2:35][CH2:36][CH2:37][CH:32]2[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][N:34]1[CH:30]([C:28]([NH:27][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:29])[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:33]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NC(=O)C1CC2CCCC2N1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Solvent: CCO
Product: CC(C)(C)NC(=O)C1CC2CCCC2N1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 2.98 g of 3(S)-(benzyloxyformamido)-1,2(S)-epoxy-4-phenylbutane and 2.1 g of N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide in 50 ml of ethanol was heated at reflux for 10 hours and the solvent was then removed by evaporation. Chromatography on silica gel using System H for the elution then gave 4.7 g of 1-[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-octahydro-cyclopenta[b]pyrrole-2-carboxamide as a mixture of four diastereomers: MS: m/e 508 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:21][C:22]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: COc1ccc(N)c(OC)c1
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c(OC)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 2,4-dimethoxyaniline gave N2-(2,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.35 (s, 1H), 8.14 (bd, 1H), 7.38 (d, 1H, J=9 Hz), 7.23 (s, 1H), 7.09 (d, 1H, J=8.7 Hz), 6.79 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=2.4 Hz), 6.49 (dd, 1H, J=2.4 and 9 Hz), 4.22 (s, 4H), 3.77 (s, 6H); LCMS: ret. time: 20.93 min.; purity: 98%; MS (m/e): 399 (MH+).
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:43]=[CH:42][C:20]([O:21][C:22]2[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:40][N:39]([CH3:41])[CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[C:19]([F:44])[CH:18]=1.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])=[CH:48][CH:47]=1>C(O)C.C1(C)C=CC=CC=1>[F:44][C:19]1[CH:18]=[C:17]([NH:16][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:49]2[CH:50]=[CH:51][C:46]([F:45])=[CH:47][CH:48]=2)=[S:57])[CH:43]=[CH:42][C:20]=1[O:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]2[CH2:32][CH2:33][N:34]([CH:37]3[CH2:40][N:39]([CH3:41])[CH2:38]3)[CH2:35][CH2:36]2)=[O:30])[CH:23]=1
Reactant: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (29.4 mg) to a solution of 4-(1-methylazetidin-3-yl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (31.8 mg) in ethanol (1.5 ml), the mixture was stirred for 10 minutes at room temperature. A solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.25 M, 0.634 ml) was added thereto, and stirring was carried out at room temperature for 30 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated, and the residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was concentrated to provide the title compound (8.0 mg, 16.9%) as white powder.