Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.CC1(C)C(C)(C)OB([C:34]2[N:35]=[CH:36][S:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:17]1([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: NC(=O)c1cc(-c2cscn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 105 °C
Yield: 42.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (50 mg, 0.112 mmol, Example 144A), Pd(Ph3P)4 (7 mg, 6.06 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (37 mg, 0.175 mmol), aqueous Na2CO3 (0.15 mL, 0.300 mmol), MeOH (1 mL) and Toluene (2 mL) were combined in a 5 ml microwave vial. The vial was sealed, flushed with nitrogen and heated to 105° C. for 4 hours in an oil bath. Additional Pd(Ph3P)4 (20 mg, 15 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (65 mg, 0.308 mmol) and aqueous Na2CO3 (0.30 mL, 0.60 mmol) were added, the vial flushed with nitrogen again and heat to 105° C. for 5 additional hours. The reaction mixture was evaporated to dryness, suspended in water and the crude product was collected by filtration through a medium porosity glass frit. The crude was washed with water, then dissolved off the frit with DMSO and purified by prep HPLC. Product containing fractions were combined and concentrated in vacuum to give 19.4 mg 7-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=407, m/e−=405, consistent with [M−H]− and [M+H]+. 1H NMR (CD3OD+CDCl3) δ ppm 9.11 (d, 1H, J=2.1), 8.91 (d, 1H, J=1.5), 8.57 (d, 1H, J=1.5), 8.26 (d, 1H, J=8.0), 7.96 (d, 1H, J=1.8), 7.72 (s, 1H), 7.32 (dd, 1H, J=7.9, 1.2), 3.90-3.50 (b, 8H). HPLC retention time 8.02 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:7][C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 71.7 %

Procedure:
5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.8 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 4.45 g, 72%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28](O)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][C@H:16]([C:28]([NH:64][C@H:63]([C:65]([NH2:67])=[O:66])[CH2:62][S:61][C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:29])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])=[CH:31][CH:32]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
1.50 g (2.59 mmol) of the compound from example 11A was dissolved in 60 ml dichloromethane. 0.940 g (2.59 mmol) S-Trityl-L-cysteinamide, 0.45 ml (2.60 mmol) N,N-diisopropylethylamine and 0.984 g (2.59 mmol) HATU were added. The reaction mixture was split into 3 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 400 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 1.72 g (1.64 mmol, 63% of theory, 88% purity) of the desired product.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:29]2[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]2)[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (190 mg, 0.50 mmol), 3,3-difluoro-pyrrolidine×HCl (143 mg, 1.00 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (10 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH3:15])[C:13]#[N:14].[C:20](OC)(=[O:23])[CH2:21][SH:22].C(N(CC)CC)C>C(O)C>[CH3:15][N:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[CH3:1])[C:13]1[S:22][CH2:21][C:20](=[O:23])[N:14]=1
Reactant: COC(=O)CS
Reactant: Cc1ccccc1OCc1ccccc1N(C)C#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccccc1OCc1ccccc1N(C)C1=NC(=O)CS1
Yield: 42.9 %

Procedure:
A solution of 6.3 g (0.01 mol) of 40% pure N-[2-(2-methylphenoxymethyl)-phenyl]-N-methyl-cyanamide, 1.1 g (0.01 mol) of methyl thioglycolate and 0.15 g of triethylamine in 100 ml of ethanol is heated under reflux for 18 hours. The mixture is concentrated and the residue is chromatographed over silica gel using cyclohexane/ethyl acetate (1:3). 1.4 g (43% of theory) of 2-{methyl-[2-(2-methylphenoxymethyl)-phenyl]-amino}-thiazol-4-one are obtained.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]([C:14]1[N:15]=[C:16](S(C)(=O)=O)[N:17]([CH3:29])[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]>C1COCC1>[CH3:10][O:11][C:12]([C:14]1[N:15]=[C:16]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:17]([CH3:29])[C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: Br[Mg]CC1CCCCC1
Reactant: COC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(CC2CCCCC2)n(C)c(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Cyclohexylmethylmagnesium bromide solution (1.77 ml; 885 μM of 0.5M solution in THF) was added dropwise to a solution of 5-benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.26 g; 738 μM) in THF (10 ml). After stirring at room temperature for 1 h, the reaction mixture was quenched by the addition of saturated ammonium chloride solution. The product was extracted into EtOAc, washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to give the title product as a colourless oil (0.040 g; 70%). LCMS: m/z=367 (MH+).
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[CH2:42](O)[CH:43]=[CH2:44].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:44]([O:10][C:11]1[C:12]2[N:13]=[CH:14][N:15]([C:38]=2[N:39]=[CH:40][N:41]=1)[C@@H:16]1[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:21])[CH3:22])[CH2:17]1)[CH:43]=[CH2:42]
Reactant: C=CCO
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C=CCOc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 89 %

Procedure:
As described for the synthesis of 3′,5-bis-O-(tert-butyldimethylsilyl)-O6-methyl-2′-deoxyinosine, the allyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and allyl alcohol (1 mL) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) over 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 46.4 mg (89% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.29. 1H NMR (500 MHz, CDCl3): δ 8.51 (s, 1H, Ar—H), 8.27 (s, 1H, Ar—H), 6.50 (t, 1H, H-1′, J=6.4), 6.16 (m, 1H, —CH═), 5.45 (dd, 1H, ═CHtrans, J=17.1, 1.5), 5.29 (d, 1H, ═CHcis, J=10.7), 5.12 (d, 2H, OCH2, J=5.4), 4.61 (m, 1H, H-3′), 4.02 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.77 (dd, 1H, H-5′, J=11.2, 2.9), 2.61 (app quint, 1H, H-2′, Japp˜6.3), 2.44 (ddd, 1H, H-2′, J=12.9, 6.1, 3.9), 0.91 (s, 18H, tert-Bu), 0.09, 0.08 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.3, 151.9, 151.6, 140.6, 132.4, 121.9, 118.5, 87.9, 84.4, 71.8, 67.5, 62.7, 41.4, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C25H45N4O4Si2 (M++H) 521.2979. found 521.2974.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[SH:8].[CH3:10][N:11]1[C:15]([C:16](O)=O)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][N:11]1[C:15]([C:16]2[S:9][C:3]3[N:4]=[CH:5][N:6]=[C:7]([SH:8])[C:2]=3[N:1]=2)=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]=[CH:12]1
Reactant: Nc1c(S)ncnc1S
Reactant: Cn1cnc(-c2ccccc2)c1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cn1cnc(-c2ccccc2)c1-c1nc2c(S)ncnc2s1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
5-Aminopyrimidin-4,6-dithiol (Intermediate 41) (1.26 g) and 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (Intermediate 3) (1.6 g) were dissolved/ suspended in pyridine (30 mL) and heated at 55° C. under an inert atmosphere. POCl3 (1.55 mL) was added dropwise over 5 minutes, after 2 hours the reaction mixture was concentrated in vacuo and 2M NaOH (15 mL) added cautiously. After stirring for 15 minutes, concentrated HCl was added to acidify to pH 5, the precipitated solid was filtered, washed with water (40 mL), diethyl ether (50 mL) then dried under high vacuum to give the title compound as a yellow solid (1.83 g, 71%);
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([C:28]([N:7]2[CH2:6][CH:5]3[CH2:1][N:2]([C:9]4[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=4)[CH2:3][CH:4]3[CH2:8]2)=[O:29])[CH:31]=1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 1. MS (ESI): mass calculated for C22H22F4N8O, 490.46; m/z found 490.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.00-7.92 (m, 1H), 7.78-7.64 (m, 2H), 7.26-7.20 (m, 1H), 7.17-7.11 (m, 1H), 5.87 (br s, 1H), 3.96-2.87 (m, 16H).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[NH:11]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12]1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[N:17]1([CH2:16][C:13]2[CH:14]=[CH:15][NH:11][C:12]=2[CH:4]=[O:5])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: c1cc(CN2CCOCC2)c[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1[nH]ccc1CN1CCOCC1
Reaction time: 0.08 h

Procedure:
To a solution of DMF (66 mmoles) in DCM there is added, dropwise, at 0° C., POCl3. After stirring for 5 minutes, a solution of the compound obtained in Step B (33 mmoles) in DCM (60 ml) is added dropwise. After stiffing for 4 hours at 0° C. and for 30 minutes at reflux, an aqueous solution of sodium acetate (110 mmoles) is added. After a further 30 minutes at reflux, aqueous 2M sodium hydroxide solution is added at ambient temperature until the pH is alkaline (9-10). The solution is stirred for 2 hours at ambient temperature, and then 300 ml of DCM are added. After extracting with DCM, the organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel (SiO2; gradient DCM/AcOEt) to yield the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[O:37]1[CH2:41][CH:40](O)[CH:39]([OH:43])[CH2:38]1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([CH:21]2[CH2:22][CH2:23][C:24]3([O:43][C@H:39]4[CH2:38][O:37][CH2:41][C@H:40]4[O:27]3)[CH2:25][CH2:26]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: OC1COCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
A mixture of 3′-fluoro-4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), tetrahydrofuran-3,4-diol (0.26 g), p-toluenesulfonic acid monohydrate (0.005 g) and toluene (50 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 3 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[O:3]1.[I:17]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:17][C:8]1[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[O:3][C:2]([CH3:16])([CH3:1])[CH2:6][C:5]=2[CH:7]=1
Reactant: II
Reactant: CCOC(=O)c1cccc2c1OC(C)(C)C2
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CCOC(=O)c1cc(I)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of ethyl 2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (2.03 g, 9.22 mmol) in methanol (40 mL) was added iodine (2.57 g, 10.14 mmol) and silver sulfate (3.45 g, 11.06 mmol). The reaction was stirred for 3 hours at room temperature and was filtered through celite to remove the solids formed. The solvent was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide ethyl 5-iodo-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (829) (3.12 g, 98%) as a red solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)(=[O:4])=[O:3].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)(=[O:3])=[O:4])=[O:28])[N:19]=1
Reactant: COc1cc(Cl)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cn1nnnc1-c1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnnn2C)n1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 0.48 g of 5-(2-aminosulfonylphenyl)-1-methyl-1H-tetrazole and 0.56 g of phenyl N-(4-chloro-6-methoxypyrimidine-2-yl)carbamate in 20 mL of dry acetonitrile at ambient temperature was added, with stirring, 0.3 mL of DBU. After stirring 16 hours the mixture was then poured into 25 g of ice followed by the addition of 10 mL of 2N hydrochloric acid. The precipitate thus formed was removed by filtration, washed with water and dried to yield 0.74 g of the desired product, m.p. 225°-227° C.
Reaction SMILES: C=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]([CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[C:34]([BH3-])#N.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1COCC1.C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:34])[CH:23]([CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:22][CH2:21]4)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2CCC1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
37 mg (1.23 mmol) paraformaldehyde in 1.8 mL THF are added to a solution of 350 mg (0.82 mmol) 6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (see Example 3.46) in 1.6 mL THF. 0.24 mL acetic acid and 1.2 mL THF are added to this mixture. Finally, 1.00 g (2.05 mmol) cyanoborohydride resin (macroporous polystyrene, load: 2.04 mmol/g) are added and the mixture is stirred for 16 h at RT. After filtration the filtrate is combined with 1.50 g (2.15 mmol) toluenesulphonic acid resin (macroporous polystyrene, load: 1.43 mmol/g), shaken for 30 min and suction filtered. The solvent is eliminated i.vac. and purification is carried out by column chromatography using HPLC-MS.
Reaction SMILES: C([Li])CCC.[CH2:6]([S:8][C:9]1[N:13]2[C:14](C)=[CH:15][CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1)[CH3:7].[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:6]([S:8][C:9]1[N:13]2[C:14]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1)[CH3:7]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCSc1ncc2cccc(C)n12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc2cnc(SCC)n12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M, 4.2 mL, 6.7 mmol) is added slowly to a solution of the title B compound, 3-ethylsulfanyl-5-methyl-imidazo[1,5-a]pyridine (1.14 g, 6.4 mmol) in anhydrous THF (7 mL) at −78° C. The resulting solution is stirred at −78° C. for 1 h and tributyltinchloride (2.0 mL, 7.4 mmol) is added. The reaction is stirred at −78° C. for 1 h further, and then allowed slowly to warm to RT overnight. The reaction is quenched by addition of saturated aqueous ammonium chloride (15 mL) and the mixture is extracted two times with ethyl acetate. The organic extracts are combined, washed with aqueous potassium fluoride solution (3 M, 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by flash column chromatography on silica using 10% ethyl acetate in hexanes as the eluant to yield 3-ethylsulfanyl-5-tributylstannyl-imidazo[1,5-a]pyridine as a dark oil: 1H-NMR (CDCl3) δ 7.51 (s, 1H), 7.38 (dd, J=8.7, 1.2, 1H), 6.71 (dd, J=6.3, 1.5, 1H), 6.63 (dd, J=8.7, 6.3, 1H), 2.98 (q, J=7.4, 2H), 1.58–1.48 (m, 6H), 1.40–1.17 (m, 15H), 0.88 (t, J=7.5, 9H); 13C-NMR (CDCl3) δ 140.27, 133.53, 132.20, 124.88, 124.76, 124.63, 121.89, 118.77, 118.65, 118.56, 32.22, 29.66, 29.37, 29.30, 29.22, 27.94, 27.79, 27.68, 27.42, 15.59, 15.52, 14.83, 14.12, 14.03, 12.71, 12.65; MS (M+1)+ 465, 466, 467, 468, 469 (tin isotope pattern).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[C:19]3[C:11](=[CH:12][N:13]=[C:14]4[C:18]=3[CH:17]=[CH:16][NH:15]4)[N:10]=[N:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(O)C>[CH3:1][C:2]1([N:8]2[C:19]3[C:11](=[CH:12][N:13]=[C:14]4[C:18]=3[CH:17]=[CH:16][NH:15]4)[N:10]=[N:9]2)[CH2:7][CH2:6][N:5]([CH2:22][CH2:21][C:20]#[N:23])[CH2:4][CH2:3]1
Reactant: C=CC#N
Reactant: CC1(n2nnc3cnc4[nH]ccc4c32)CCNCC1
Solvent: CCO
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCN(CCC#N)CC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
A mixture of 1-(4-methyl-piperidin-4-yl)-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (75.0 mg, 0.29 mmol) and acrylonitrile (95.5 μL, 1.45 mmol) in ethanol was stirred at 80° C. for 5 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography on silica gel (gradient: 0 to 4.5% [2M NH3 in methanol] in DCM) to afford 64.0 mg (71%) of 3-[4-methyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-piperidin-1-yl]-propionitrile. LCMS (Method A, ESI): RT=1.91 min, m+H=310.3; 1H NMR (400 MHz, DMSO) δ: 12.41 (s, 1H), 9.04 (s, 1H), 7.59 (t, 1H), 7.08 (m, 1H), 2.85 (m, 2H), 2.66 (m, 4H), 2.58 (m, 2H), 2.49 (m, 2H), 2.11 (m, 2H), 1.85 (s, 3H).