Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ClC1C2C(C3C=CC(OC4C=CC=CC=4)=C(C=3)C#N)=CN([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2N=CN=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[C:10]([C:29]3[CH:30]=[CH:31][C:32]([O:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[C:27]([O:26][CH3:25])[CH:28]=3)=[CH:9][N:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:24][CH:19]4[CH3:20])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(I)c4c(Cl)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1
Agent: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(Cl)ncnc43)CC2)CC1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC#N
Product: COc1cc(-c2cn([C@H]3CC[C@H](N4CCNCC4C)CC3)c3ncnc(Cl)c23)ccc1Oc1ccccc1

Procedure:
The title compound (223 mg, 64%) was prepared from trans-4-chloro-5-iodo-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.655 mmol) and 2-(3-methoxy-4-phenoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (235 mg, 0.727 mmol) in a similar manner to that described for the preparation of trans-5-(4-chloro-7-(4-(4-methylpiperazino)cyclohexyl)-7H-pyrrolo[2,3-d ]pyrimidin-5-yl)-2-phenoxybenzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 8.67(s, 1H), 8.04(s, 1H), 7.32(m, 4H), 7.12(d, 1H), 7.08(d, 1H), 6.88(d, 2H), 4.71(m, 1H), 3.80(s, 3H), 2.2-2.6(m, 9H), 2.15(s, 3H), 1.9-2.1 (m, 6H), 1.49(m, 2H); MS MH+532.4; RP-HPLC (Hypersil HS, 5 μm, 100 Å 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 9.58 min.
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].[NH4+].[OH-].C(OCC)C>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2cnccc12
Temperature: 100 °C

Procedure:
To a stirring mixture of methyl 4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (100 mg) in DMF (0.5 mL) was added CuCN (150 mg). The resulting mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature. To this mixture was added a 10% NH4OH solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ether was followed. The organic layers were dried over MgSO4, filtered and concentrated under reduce pressure. The crude product mixture was purified by silica gel column chromatography to give methyl 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate. Method[1], MS (ESI) 352.0 [M+H], Retention time=1.343 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]([Cl:17])[C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[SH:10]>Br>[Cl:17][C:11]1[CH:12]=[C:13]([OH:15])[CH:14]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[SH:10]
Reactant: COc1cc(Cl)c(Cn2ccnc2S)c(Cl)c1
Agent: Br
Product: Oc1cc(Cl)c(Cn2ccnc2S)c(Cl)c1
Yield: 67.3 %

Procedure:
A mixture of 1-[2',6'-dichloro-4'-methoxybenzyl]2-mercaptoimidazole (1 g) in concentrated aqueous hydrobromic acid (50 ml) was heated at reflux under argon for 1.25 hr, and then cooled. The product was collected by filtration. Washing with concentrated aqueous hydrobromic acid and water and drying yielded 0.64 g (60%) of product as light yellow crystals: mp 235° (dec).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[N:10][C:6]=2[C:5]([F:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH:23]=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+]>O1CCOCC1.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]>[Cl:19][C:18]1[C:11]([C:9]2[S:8][C:7]3[C:2]([NH:28][C:24]4[CH:23]=[C:22]([CH3:21])[N:27]=[CH:26][N:25]=4)=[N:3][CH:4]=[C:5]([F:20])[C:6]=3[N:10]=2)=[C:12]([CH:15]=[CH:16][CH:17]=1)[C:13]#[N:14]
Reactant: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
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(Nc2ncc(F)c3nc(-c4c(Cl)cccc4C#N)sc23)ncn1
Temperature: 80 °C
Yield: 36.1 %

Procedure:
A mixture of 2-(4-bromo-7-fluorothiazolo[5,4-c]pyridin-2-yl)-3-chlorobenzonitrile (0.110 g, 0.30 mmol), 6-methylpyrimidin-4-ylamine (35 mg, 0.32 mmol), XantPhos (0.018 g, 0.03 mmol) and Cs2CO3 (247 mg, 0.75 mmol) in dioxane (2.5 mL) was degassed with a stream of argon. Pd2(dba)3 (0.014 g, 0.015 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours in a sealed vial. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with EtOAc (50 mL). The filtrate was concentrated to dryness under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc in DCM, then triturated with diethyl ether (×2), to afford the title compound as a pale yellow solid (43 mg, 36% yield). 1H NMR (400 MHz, CDCl3): δ 8.73 (d, J=1.2 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 7.86-7.76 (m, 3H), 7.66 (t, J=8.0 Hz, 1H), 7.57 (br s, 1H), 2.56 (s, 3H). LCMS (Method C): RT=3.31 min, m/z: 397 [M+H+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(CO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1NS(=O)(=O)c1ccc(COC2CCCCO2)cc1
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
4-Hydroxymethyl-N-(2-methoxyphenyl)benzenesulfonamide (99.6 mg, 0.34 mmol) was dissolved in methylene chloride (3 ml) to which, with cooling in an ice bath, were subsequently added 3,4-dihydro-2H-pyrane (48 μl, 0.51 mmol) and a catalytically effective amount of p-toluenesulfonic acid monohydrate. After 90 minutes of stirring at the same temperature, the reaction solution was mixed with saturated sodium bicarbonate aqueous solution (5 ml) and extracted with ether. The resulting organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate, and the solvent was removed by evaporation. Thereafter, the thus obtained light yellow oily material was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain 117 mg (91.2%) of the title compound in the form of colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:35][CH2:36][CH:37]([OH:40])[CH2:38][N:39]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([O:19]CC)=[O:18])[CH:5]=[C:6]([C:8]([CH3:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:15]([NH:22][C:23](=[O:43])[CH2:24][NH:25][C:26](=[O:42])[C:27]2[CH:32]=[C:31]([NH:33][C:34]3[NH:39][CH2:38][CH:37]([OH:40])[CH2:36][N:35]=3)[CH:30]=[C:29]([OH:41])[CH:28]=2)[CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[C:6]([C:8]([CH3:13])([CH3:14])[C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(C)C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC(C)(c1cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c2cc(O)cc(NC3=NCC(O)CN3)c2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.785 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (165 mg, 3.932 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue and the residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL) for 15 min. The aqueous layer was separated, acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to afford the desired product, after lyophilization, as a colorless lyophilized powder (277.7 mg). LC-MS analysis of the residue shows the desired product: (3S)-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoic acid's mass: m/z 600 (35ClM+H), and m/z 602 (37ClM+H); Calcd for C26H29ClF3N5O6: 599.99.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH:18]([N:21]=[C:22]=[O:23])([CH3:20])[CH3:19]>>[CH:18]([NH:21][C:22]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:23])([CH3:20])[CH3:19]
Reactant: CC(C)N=C=O
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Product: CC(C)NC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The procedure of Example 10 was used to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and isopropyl isocyanate. The product crystallized as a white solid, mp 93°-96° C. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: NC(=NO)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: CO
Product: NC(=NO)c1ccc(-c2ccc(N)cc2)o1

Procedure:
A mixture of 55 g (0.19 mole) of the compound of Example II, 500 ml of CH3OH and one teaspoon of 5% Pd/C (50% H2O) was shaken on the Parr apparatus with the theoretical amount of H2 being absorbed. The catalyst was removed by filtration and the solvent removed on the Calab evaporator leaving a residual solid which was washed in refluxing acetonitrile. The resulting solid was then washed in 1 N NaOH solution and air dried to yield 22 g (52%). An analytical sample was prepared by drying a sample at the temperature of refluxing CHCl3 in the vacuum pistol, m.p. 180°-183°.
Reaction SMILES: [CH:1]([O:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][OH:10])([CH3:3])[CH3:2].O[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([O:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17])([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)OCOCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OCOCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
A mixture of [3-(isopropoxymethoxy)propanol (5.3 g, 35.8 mmol), N-hydroxyphthalimide (5.83 g, 35.8 mmol) and triphenylphosphine (10.48 g, 40 mmol) in dry tetrahydrofuran (75 ml) at 0°-5° C.; was treated with a solution of diethyl azodicarboxylate (6.96 g, 40 mmol) in dry tetrahydrofuran (15 ml) over 15 min. The reaction mixture was stirred at ambient temperature for 18 hr. The solvent was removed in vacuo and the residue was dissolved in diethyl ether (100 ml) and cooled to 5° C. for 2 hr. The solid was filtered off, the filtrate evaporated in vacuo, and the residue purified by column chromatography on silica eluting with hexane:ethyl acetate (70:30) to give the title compound as an oil (9.3 g, 88%). νmax (Film) 2980, 2940, 2900, 1740, 1475 and 1380 cm-1 ; δH (CDCl3) 1.17 (3H, s, CH3), 1.19 (3H, s, CH3), 2.06 (2H, quintet, J=6.3 Hz CH2CH2CH2), 3.77 (2H, t, J=6.3 Hz, CH2OCH2OCH(CH3)2), 3.88 (1H, septet, J=6.3 Hz, OCH(CH3)2), 4.32 (2H, t, J=6.3 Hz CH2ON), 4.73 (2H, s, OCH2O), 7.78 (4H, m, ArH). (Found: C, 16.53; H, 6.59; N, 4.71%: C15H19NO5 requires: C, 16.42; H, 6.52; N, 4.77%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=2[N:7]=1>C(O)=O>[CH:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=3[CH2:10][CH2:11][C@@H:12]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]2=[N:5][CH:4]=1
Reactant: COC(CNC1=Nc2ccccc2CC[C@H]1NC(=O)OCc1ccccc1)OC
Solvent: O=CO
Product: O=C(N[C@@H]1CCc2ccccc2-n2ccnc21)OCc1ccccc1
Temperature: 100 °C
Yield: 84.7 %

Procedure:
Dissolve benzyl N-[(3R)-2-(2,2-dimethoxyethylamino)-4,5-dihydro-3H-1-benzazepin-3-yl]carbamate (9.78 g, 24.61 mmol) in formic acid (60 mL, 96%) and heat at 100° C. for 1.5 hours. Allow the mixture to cool and remove the black sediment by filtering it through a glass wool plug. Concentrate the filtrate under reduced pressure, pour it into water, and basify it with 1M NaOH. Add ethyl acetate to the resulting precipitate and separate the organic layer. Extract the aqueous layer with ethyl acetate. Combine, wash (brine), dry over sodium sulfate, and concentrate the organic layers under reduced pressure to give the title compound (6.95 g, 85%): MS (m/z): 334 (M+1), 97.8% ee, Retention time for Isomer 1 (R Isomer), 4.58 min; Isomer 2 (S Isomer), 3.20 min. (Chiralpak AD-H column; 100% EtOH with 0.2% dimethylethylamine; flow rate 1.0 mL/min; 225 nM).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+].CO>>[C:32]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([N:28]([CH3:29])[CH3:30])=[N:25][C:24]=4[CH:31]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7])[N:9]=1)#[N:33]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc2cc(Oc3ccc4c(C#N)nc(C(=O)NCC(=O)O)c(O)c4c3)ccc2o1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1-cyano-6-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (55 mg, 0.12 mmol), glycine (186 mg, 2.47 mmol) and 0.5 M sodium methoxide/methanol (4.7 mL) was refluxed for twenty-five hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (35 mL) and washed with dichloromethane (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (44 mg): MS: (+) m/z 448.27 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([CH2:14]OS(C)(=O)=O)[C@@H:4]([C:20]([O:22][CH3:23])=[O:21])[O:3]1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C=O)C>[N:25]([CH2:14][C@@H:5]1[C@@H:4]([C:20]([O:22][CH3:23])=[O:21])[O:3][C:2]([CH3:24])([CH3:1])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1CN=[N+]=[N-]
Temperature: 70 °C
Yield: 31.3 %

Procedure:
Compound XXXVII (0.30 g, 0.80 mmol) was dissolved in DMF (10 mL) followed by the addition of NBu4Br (0.092 g, 0.28 mmol) and then NaN3 (0.15 g, 2.32 mmol). The mixture was heated at 70° C. for 7 h. Water (30 mL) was added to the cooled reaction mixture and it was extracted with EtOAc (3×20 mL). The organic phase was separated, dried over Na2SO4 and evaporated. The residue was purified on a silica gel column (3:1 hexane/EtOAc→1:1 hexane/EtOAc) to yield (4R,5S)-3-tert-butyl 5-methyl 4-(azidomethyl)-2,2-dimethyloxazolidine-3,5-dicarboxylate XXXVIII (0.078 g, 0.25 mmol, 31%). ESIMS found for C13H22N4O5 m/z 337 (M+Na).
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[O:24][CH:23]=[C:22]([CH:25]=[O:26])[CH:21]=1>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:21]=[C:20]([Si:19]([CH3:28])([CH3:27])[CH3:18])[O:24][CH:23]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCCCC/C=C/CCc1ccccc1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCC/C=C/CCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (E)-9-phenylnon-6-enyl magnesium bromide (0.861 mmol, prepared from 0.242 g, 0.861 mmol, of (E)-1-bromo-9-phenylnon-6-ene and 2.88 mmol magnesium) in tetrahydrofuran (10 ml) at 0° under argon was added dropwise, 5-trimethylsilyl-3-furaldehyde (0.145 g, 0.861 mmol) in tetrahydrofuran (5 ml). The solution was warmed to room temperature, stirred for 5 hours, quenched with 5% ammonium chloride and extracted into ethyl ether. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give yellow oil. Purification by flash chromatography (silica, 5 to 20% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=O)[CH2:3]2.[OH-].[K+].[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)([O-:15])=[O:14]>O.CO>[N+:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:4]1[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CN4CCC3CC4)c2c1
Reaction time: 48 h

Procedure:
44.8 mmol of 1-azabicyclo[2.2.2]octan-3-one hydrochloride (3-quinuclidinone hydrochloride) and 112 mmol of potassium hydroxide are added to a solution of 22.4 mmol of 5-nitro-1H-indole in 100 ml of water/methanol (1/1), and the mixture is stirred at the boiling point for 48 hours. The crystals which deposit on cooling of the reaction solution are filtered off, washed and dried, giving 3-(5-nitro-1H-indol-3-yl)-1-azabicyclo[2.2.2]-oct-2-ene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]CC)=O)=[C:13]([CH2:22]Br)[N:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[NH2:24][C:25]1[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]3[CH2:22][N:24]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=4)[C:17](=[O:19])[C:14]3=[CH:15][CH:16]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: N#CCn1cc(N)cn1
Reactant: CCOC(=O)c1ccc(-c2cnc(OC)c(OC)c2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc3c(n2)CN(c2cnn(CC#N)c2)C3=O)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
As shown in step 8-iv of Scheme 8, a solution of the above mixture (Compound 2029, 2.2 g, about 60% pure) in DMF (40 mL) at 0° C. was added dropwise over 2 hours to a suspension of 2-(4-amino-1H-pyrazol-1-yl)acetonitrile (844 mg, 6.9 mmol) and sodium carbonate (732 mg, 6.9 mmol) in DMF (20 mL). After addition was complete, the reaction mixture was stirred at 0° C. for 2 hours and heated at 80° C. for 15 hours. Additional sodium carbonate (732 mg) was added and the reaction mixture was heated at 90° C. for an additional 7 hours. After cooling, the mixture was poured into water and a precipitate formed. The solid was collected by filtration, washed with methyl t-butyl ether, and dried under high vacuum to provide 2-(4-(2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-1H-pyrazol-1-yl)acetonitrile (Compound 25, 450 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[N:27]1[CH:32]=[C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:24])([F:25])[F:26])[CH:3]=2)[CH:30]=[N:29][CH:28]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3cncnc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 45.1 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.10 g) and pyrimidine-5-boronic acid (0.053 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (0.8 ml) with tetrakis(triphenylphosphine)palladium (0.012 g) to obtain the title compound (0.045 g) as a colorless solid. MS (ISN): 466.1 (M−H)−
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.C(N(CC)CC)C>ClCCl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCCCCCn1c2ccccc2c2ccccc21
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 30 mmol of methacryloyl chloride in 10 ml of dichloromethane was added dropwise to a solution of 25 mmol of N-(6-hydroxyhexyl)-carbazole and 30 mmol of triethylamine in 100 ml of dry dichloromethane. Thereafter, the reaction mixture was stirred for 3 hours at room temperature and then worked up by washing it with 2N sodium hydroxide solution and water. After the reaction mixture had been evaporated down, the 6-(N-carbazolyl)-hexyl methacrylate formed was isolated by column chromatography over silica gel (eluent: dichloromethane). The 6-(N-carbazolyl)-hexyl methacrylate thus obtained in 70% yield was in the form of a colorless oil and had the following characteristic data: