Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[C:38]([O:51][CH2:52][O:53][CH3:54])[CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:8]=3)[NH:3][C:2]=2[C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=2[O:51][CH2:52][O:53][CH3:54])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COCOc1cc(OC)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl[Pd]Cl
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCOc1cc(OC)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in International patent application WO2004087714, from commercially available methyl indole-6-carboxylate), 2-[4-methoxy-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 eq) and 2 M Na2CO3 (aq) (6 eq) in dioxane (0.15 M) was prepared. Then the mixture was degassed with nitrogen and bis(triphenylphosphine)palladium (II) chloride (0.2 eq) was added. The resulting mixture was immersed in a pre-heated oil bath at 110° C. for 2 h. The mixture was cooled, diluted with EtOAc, washed with 1 N HCl (aq), brine, dried (Na2SO4), filtered and the solvent removed in vacuo. The crude was purified by automated FC (PE/EtOAc 9:1) to afford the product (93%). (ES+) m/z 424 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[C:19]([NH:18][C:10]([NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[N:24][CH:21]([CH3:23])[CH3:22])#[N:20]
Reactant: CC(C)N
Reactant: N#CN=C(Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Product: CC(C)N=C(NC#N)Nc1cc(Cl)cc(Cl)c1
Yield: 43 %

Procedure:
N-(3,5-Dichlorophenyl)-N'-cyano-O-phenylisourea (0.98 mmol, 300 mg) and isopropylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was crystallized from ethyl acetate/heptane 1:3 to give the title compound (115 mg, 43%) as white crystals. Mp 156-158.5° C.; 1H-NMR (CDCl3): δ 1.21 (d, 6H), 4.03 (m,1H), 4.70 (br d,1H), 7.16 (m, 2H), 7.29 (m,1H), 7.47 ppm (br,1H); MA calc for C11H12Cl2N4 : C, 48.73%; H, 4.46%; N, 20.66%. Found: C, 48.76%; H, 4.49%; N, 20.38%.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.CCN(CC)CC>C(Cl)Cl>[CH:33]1([C:36]([N:1]2[CH2:2][CH:3]([CH2:5][C:6]3[N:7]([CH3:32])[C:8]4[C:13]([N:14]=3)=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=[C:10]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH2:30][CH3:31])[N:9]=4)[CH2:4]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C4CC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (108 mg, 0.25 mmol), cyclopropane carbonyl chloride (27 mg, 0.25 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) followed by triturating with Et2O affording 825 as a white solid (107 mg, 85%). LCMS (method I): RT 3.33 min, [M+H]+ 501.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.98 (1 H, m), 7.76-7.73 (1 H, m), 7.32-7.22 (2 H, m), 4.53 (1 H, t, J=8.31 Hz), 4.45-4.20 (4 H, brd s), 4.28 (1 H, t, J=9.30 Hz), 4.09 (1 H, dd, J=8.45, 5.41 Hz), 3.86 (5 H, t, J=4.77 Hz), 3.77 (3 H, s), 3.34-3.33 (3 H, m), 3.18-3.15 (2 H, m), 1.45-1.43 (4 H, m), 0.99-0.98 (2 H, m), 0.77-0.76 (2 H, m)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>[Pt](=O)=O.C(O)(=O)C>[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC1CCNCC1

Procedure:
75 g of 4-pyridylacetic acid hydrochloride are treated with 750 ml of glacial acetic acid (50% strength), 6 g of platinum dioxide are added and the mixture is hydrogenated at 3 bar and room temperature in the course of 3 hours. The catalyst is filtered off with suction and the mother liquor is concentrated to dryness in vacuo. The residue is triturated with acetone and filtered off with suction. It is washed twice with acetone and once with ether.
Reaction SMILES: [C:1](/[C:3](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)/[C:4]([O:6][CH2:7][CH:8]1[CH2:12][O:11]C(C)(C)[O:9]1)=[O:5])#[N:2].C(N(CC)CC)C>C1COCC1.CO>[C:1](/[C:3](=[CH:15]\[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)/[C:4]([O:6][CH2:7][CH:8]([OH:9])[CH2:12][OH:11])=[O:5])#[N:2]
Reactant: CN(C)c1ccc(/C=C(\C#N)C(=O)OCC2COC(C)(C)O2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(/C=C(\C#N)C(=O)OCC(O)CO)cc1
Reaction time: 20 h
Yield: 75 %

Procedure:
Compound 13 (0.5 g, 1.5 mmol) was dissolved in a mixture of THF/MeOH (1:1) and DOWEX-H+ resin (0.10 g) was added and the heterogeneous mixture was stirred for 20 hours. The DOWEX-H+ resin was removed by filtration and triethylamine (50 mg, 0.5 mmol) was added and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (100% ether) to give compound 14. 14: 75% yield; bright yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.94 (d, 2H, J=9.1 Hz), 6.69 (d, 2H, J=9.2 Hz), 4.42-4.32 (m, 2H), 4.05 (m, 1H), 3.80-3.70 (m, 2H), 3.12 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 199.0, 164.8, 155.5, 154.0, 134.6, 119.4, 117.9, 111.8, 111.7, 92.8, 70.3, 70.2, 66.9, 66.8, 63.6, 63.5, 40.3, 40.2; HRMS Calc for C15H18N2O4 (M+H)+ 291.1345 Found 291.1361.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([S:14](Cl)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O>CCOCC.N1C=CC=CC=1>[C:1]1([S:7][S:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: Sc1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=S(Sc1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 2.2 g. (20 mmol) thiophenol in 30 ml. dry ether one adds 1.8 g. pyridine and adds dropwise thereto, with cooling, a solution of 3.2 g. (20 mmol) benzenesulphinic acid chloride in 20 ml. dry ether. One allows to stir further for 10 min., pours into dil. sulphuric acid, separates off the organic phase, dries and evaporates. There remain 3.2 g. of the title compound (68% of theory) of the m.p. 69°-70° C. (from ligroin).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[Br:27]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:27][C:9]1[CH:8]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:26])[C:16]2[O:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]3[C:23](=[O:25])[NH:24][C:10]=1[C:11]=23
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1cc(Br)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (2.50 g, 7.18 mmol) in tetrahydrofuran (47 mL) was treated with N-bromosuccinimide (1.40 g, 7.89 mmol) and stirred at room temperature for 1 h, at which time the reaction mixture was treated with additional N-bromosuccinimide (0.70 g, 3.93 mmol) and stirred at 45° C. for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) gave the desired product (3.0 g, 98%) as a single enantiomer. LCMS calculated for C19H16BrN4O3 (M+H)+: m/z=427.1, 429.1. found: 426.8, 428.8.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.[NH:29](C(OC(C)(C)C)=O)[C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
On the other hand, 2 mmole of Boc-Ala, the 36th amino acid in the amino acid sequence, was dissolved in 5 ml ml of DCM. In an amino acid activating vessel, 2 ml of DCC (0.5M DCM solution) was added to the resulting solution They were reacted for 5 minutes. Thereafter, the reaction product was treated in the same manner as in the Boc-Phe After addition of DMF and subsequent concentration under a nitrogen gas stream, the resulting concentrate was transferred to a reaction vessel so as to conduct a reaction for 20 minutes. The reaction mixture was then washed with 8 ml of DCM (6 times, each, for 20 seconds) and filtered to obtain Boc-Ala-Phe-resin.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH:18]=[C:17]([F:33])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=[O:38])[CH3:37]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:22][C@@H:23]([NH:25][C:36](=[O:38])[CH3:37])[CH3:24])[CH:18]=[C:17]([F:33])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (159 mg) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound as white crystals (73.5 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][C:20](C(OCC)=O)=[C:21]([OH:22])[C:13]1=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]1[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:13]1=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C(O)c2cc3cc(OCc4ccccc4)ccc3n2CC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 220 °C
Yield: 79.7 %

Procedure:
The reaction mixture of ethyl 2-(benzyloxy)-9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carboxylate (1.22 g, 3.36 mmol) in acetic acid (36 mL) and H2O (3 mL) was heated at 220° C. for 10 min under microwave irradiation. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound (780 mg) as a yellow solid. LCMS m/z=292.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.45 (m, 2H), 2.73 (t, J=6.4 Hz, 2H), 4.23 (t, J=5.9 Hz, 2H), 5.11 (s, 2H), 7.15 (dd, J=8.9, 2.4 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.22 (s, 1H), 7.25-7.30 (m, 1H), 7.30-7.35 (m, 1H), 7.36-7.42 (m, 2H), 7.45-7.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]Br.[NH3:25]>CO>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:25]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1
Reactant: N
Reactant: Cc1nnc(CBr)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CO
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 8, 2',5-dichloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with a saturated solution of ammonia in methanol to give 8-chloro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4] benzodiazepine of melting point 225°-228° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]1=2.B.C1COCC1.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH:10]2[CH:5]([CH:6]=[C:7]([OH:11])[CH:8]=[CH:9]2)[CH:4]2[CH2:12][CH2:13][CH:14]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:3]12
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NCc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1C2C=CC(O)=CC2C2CCC(NCc3ccccc3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 4-methyl-3-phenylmethylimino-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (14.0 g) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A solution of 1M borane/THF in THF (145 ml) was added in a dropwise manner. The mixture was stirred for 1 hour while it was slowly warmed to room temperature. The mixture was cooled back to 0° C. and trifluoroacetic acid was added in a dropwise manner. The solution was stirred for 15 minutes, neutralized with 10% NaOH (Aq), extracted with CH2Cl2, dried (Na2SO4) and concentrated to give 1,2,3,3a,4,8a-hexahydro-4-methyl-3-phenylmethylaminocyclopent[b]indol-7-ol (14 grams).
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C:4]2([NH:8][CH:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28].[S:29](=[O:33])(=[O:32])([OH:31])[OH:30]>CC#N>[S:29](=[O:31])(=[O:30])([OH:33])[OH:32].[CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([NH:8][C@@H:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2CCC3(CCN(C)C3=O)N2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc([C@H]2CC[C@@]3(CCN(C)C3=O)N2)n1
Reaction time: 2 h

Procedure:
A similarly prepared sample was recrystallised from diethyl ether and isohexane to give the free base form of the title material as a colorless solid with a melting point of 66-67° C. Similarly prepared 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one with a diastereomeric excess of approximately 92% (49 g, 125.51 mmol) in MeCN (700 mL) was suction filtered through a shallow pad of Hyflo to give a clear yellow solution. To this rapidly stirred solution at 50° C. was added 7.5M sulphuric acid (17.6 mL, 132 mmol) over 5 seconds to give a solution which quickly crystallized. The mixture was left to stand at ambient temperature for 2 h then filtered and washed with acetonitrile/Et2O (1:1) (200 ml) then Et2O (150 ml) and dried 50° C. to give the title material (E2) in an 82:1 ratio of (2R,5S) and (2S,5S) isomers (50.6 g) assessed by NMR.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+]>CO>[O:15]=[C:13]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:14]1=2
Reactant: CCOC(=O)c1n[nH]c2c1C(=O)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2c1C(=O)CCC2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (purity 90%, 1.84 g, 8.0 mmol) in methanol (20 mL) is treated with 10 N NaOH (4 mL) and stirred under nitrogen at 60° C. for 90 min. The solvent is evaporated under reduced pressure and the residue is dissolved in water (30 mL), treated with brine (30 mL) and acidified to pH 2 with conc. hydrochloric acid to produce a white precipitate. The mixture is cooled to 0° C. The precipitate is filtered, washed with water (5 mL), and dried in a vacuum oven to give 4-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid. 1H NMR (DMSO-d6) 2.18 (quintet, J=6.2 Hz, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.2 Hz, 2H).
Reaction SMILES: [CH:1]1([CH:6]([NH:14][C:15](=O)OC)[C:7]([N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[CH:1]1([CH:6]([NH:14][CH3:15])[CH2:7][N:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)NC(C(=O)N1CC(O)C1)C1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(CN1CC(O)C1)C1CCCC1
Temperature: 45 °C
Yield: 102.6 %

Procedure:
To a solution of methyl 1-cyclopentyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate (Compound K2.1) (1.89 g, 7.37 mmol) in THF (50 mL) was a 1M solution of LAH in THF (30 mL, 30.0 mmol) dropwise added (over approximately 5 min) at rt under a nitrogen atmosphere. The resultant mixture was stirred at rt for 30 min and heated at 45° C. over night. Additional LAH in THF (1M solution, 10 mL) was added and the mixture was heated at 65° C. for 1 day. The mixture was diluted with Et2O (150 mL) and the reaction was quenched with Na2SO4×10H2O. The mixture was filtered and a HCl solution in EtOH was added (1.25N, 15 mL) to the filtrate. The filtrate was concentrated under reduced pressure and the residue was co-evaporated with MeOH to give the title compound (1.5 g, 75.0%). The obtained crude product was used without further purification. LCMS (M+H)+: 199.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1OCc1ccccc1
Yield: 47.8 %

Procedure:
To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and ethyl 4-bromobutyrate (2) (5.6 g, 28.7 mM) in dried acetone (100 mL) was added anhydrous ground potassium carbonate (6.0 g, 44 mM) and the resultant mixture heated at reflux under nitrogen until TLC analysis showed the absence of the starting phenol. Flash chromatography (silica gel, 15% ethyl acetate/hexane as eluant) of the filtered and concentrated mixture yielded 3.0 g of product (3) as a clear oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][C:24]3[C:25]4[S:32][C:31]([C:33]5[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=5)=[CH:30][C:26]=4[N:27]=[CH:28][N:29]=3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>CS(C)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:37][C:36]2[CH:35]=[CH:34][C:33]([C:31]3[S:32][C:25]4[C:24]([NH:23][C:19]5[CH:18]=[C:17]6[C:22](=[CH:21][CH:20]=5)[NH:14][CH:15]=[CH:16]6)=[N:29][CH:28]=[N:27][C:26]=4[CH:30]=3)=[CH:40][CH:39]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CS(C)=O
Product: O=C(c1ccco1)N1CCN(Cc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)CC1

Procedure:
The title compound was prepared furan-2-yl-piperazin-1-yl-methanone and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d; M. P. 167-174° C.; LC-MS: 535 (MH+); HPLC RT: 5.24 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=O)=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].S(Cl)([Cl:24])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([Cl:24])=[O:21])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)Cl)cc3c2n1

Procedure:
184 mg of 8-hydroxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 18) is refluxed for 3 hours in 5 ml of thionyl chloride with one drop of dimethylformamide. After concentration, the mixture is further reacted without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]CC2C=CC(Cl)=CC=2F)=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.C[S-].[Na+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(Cc2cc(Cl)ccc2O)n1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 75.6 %

Procedure:
A mixture of ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}-phenyl)methyl]-2-pyridinecarboxylate (453 mg), sodium thiomethoxide (370 mg) and dimethylformamide (5 ml) was stirred at 100° C. for 2.5 hours. After cooling water (30 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The aqueous layer was acidified with conc. hydrochloric acid and extracted with ethyl acetate (2×25 ml). The combined extracts were washed with water (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was washed with water and recrystallised from ether to afford the title compound (208 mg, 76%) as a pale buff solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccc(Cl)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylboronic acid to give [1-(3-chloro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 365(MH+).