Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:23]3[CH:24]=[N:25][CH:26]=[CH:27][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[N:19]([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH:18]=2)[CH:20]=1
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example B11, 102.8 mg of 4-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25](O)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][NH2:39])=[CH:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=4)[C:25]([NH:39][CH2:38][CH2:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)=[O:26])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)O)c1
Reactant: NCCc1ccncc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cncc(C(=O)NCCc2ccncc2)c1
Yield: 60 %

Procedure:
To solution of 5-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-nicotinic acid (40 mg, 0.098 mmol), 2-pyridine-4-yl-ethylamine (24.06 mg, 0.196 mmol) and DMAP (24.06 mg, 0.196 mmol) in DMF was added PyBOP (102.7 mg, 0.196 mmol) at room temperature, and stirred. Reaction mixture was poured onto ice cold water; diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 5-[2-(4-adamantan-1-yl-phenoxy)acetylamino]-N-(2-pyridine-4-yl-ethyl)nicotinamide as a colorless solid (30 mg, 60% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].N.CO.O1CCCC1.CO>[Ni].O>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=1)=[O:13])[CH2:6]2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(CN)cc3C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (0.04 g, 0.115 mmol) and 7M ammonia-methanol/tetrahydrofuran/methanol (4 mL) were added to Ra—Ni 2800, water slurry (0.080 g, 1.363 mmol) in a 50 ml pressure bottle and stirred for 16 hours at 30 psi and room temperature. The mixture was filtered through a nylon membrane, concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, Methanol-d4) δ ppm 7.76-7.79 (m, 2H), 7.60-7.63 (m, 2H), 7.31-7.35 (m, 3H), 4.82 (s, 4H), 3.86 (s, 2H), 3.30-3.33 (m, 2H), 1.53-1.75 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([N:16]2[C@@:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C@@:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([CH3:29])[N:18]=[C:17]2[C:37]2[CH:38]=[N:39][C:40]([C:46]([CH3:47])([CH3:49])[CH3:48])=[CH:41][C:42]=2[O:43][CH2:44][CH3:45])=[O:15])[CH2:12][CH2:13]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A solution of {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (220 mg, 0.304 mmole, example 203) in dichloromethane (6 mL) was treated with trifluoroacetic acid (6 mL) at 0° C. and allowed to stir for 2 h before concentrated to dryness under reduced pressure. The residue was then taken up in dichloromethane (100 mL), washed with aqueous sodium carbonate (2×15 mL), water (15 mL) and concentrated to give the title compound (174 mg). HR-MS (ES, m/z) calculated for C34H42Cl2N5O2 [(M+H)+] 622.2710, observed 622.2714.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([C:19](=[S:21])[NH2:20])[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)C>[CH:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([C:19]3[S:21][CH:23]=[C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:20]=3)[CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=S)c1cnn(C2CCCCC2)c1-c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cnn(C3CCCCC3)c2-c2ccc(F)cc2)n1
Yield: 83.5 %

Procedure:
A solution of the compound (236 mg, 0.78 mmol) obtained in step 2 and ethyl 4-chloroacetoacetate (0.126 ml, 0.93 mmol) in ethanol (4 mL) was stirred at 90° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from hexane to give ethyl 2-(2-(1-cyclohexyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetate (269 mg, 0.651 mmol, 84%) as a white powder.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH:6]1([CH2:9][N:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]2=[O:17])[CH2:8][CH2:7]1>CN(C=O)C>[Br:3][C:13]1[CH:14]=[CH:15][N:10]([CH2:9][CH:6]2[CH2:8][CH2:7]2)[C:11](=[O:17])[CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1cc(O)ccn1CC1CC1
Solvent: CN(C)C=O
Product: O=c1cc(Br)ccn1CC1CC1
Temperature: 110 °C
Yield: 92.8 %

Procedure:
Phosphorus oxybromide (5.4 g, 18.9 mmol) was added to a solution of intermediate D2 (1.42 g, 8.6 mmol) in DMF (140 ml) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were dried (Na2SO4) and the solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D3 (1.82 g, 93%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][N:22]1[C:34]2[CH:33]=[CH:32][C:31]([CH:35]=O)=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:35][C:31]2[CH:32]=[CH:33][C:34]3[N:22]([CH3:21])[C:23]4[C:28]([C:29]=3[CH:30]=2)=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1ccc2c(c1)c1ccccc1n2C

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 9-methyl-9H-carbazole-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 444.02 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH3:9][N:10](C)[CH:11]=O.C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:10]([CH3:11])[CH3:9])[S:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CN(C)Cc1cc(Br)cs1

Procedure:
A mixture of 4-bromo-2-thiophenecarboxaldehyde (4.8 g), dry dimethylformamide (4.3 ml) and 98% formic acid (1.4 ml), was heated at 120° for 30 h. The cooled mixture was poured into water (100 ml) and basified with anhydrous sodium carbonate. Diethyl ether (2×100 ml) was added and the ethereal solution was extracted with dilute hydrochloric acid (50 ml). The aqueous solution was basified with anhydrous sodium carbonate and extracted with diethyl ether (200 ml). The ethereal extracts were distilled to give the title compound (2.5 g) as a colourless oil, b.p. 70°/0.01 mm.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][CH2:14][CH3:15])=[CH:7][C:8](=[O:12])[O:9]2)=[C:4]2[O:16][C:17]([CH3:21])([CH3:20])[CH:18]=[CH:19][C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(OC)[O:29][CH2:30]/[C:31](/[CH3:34])=[CH:32]/[CH3:33]>ClCCl>[CH3:34]/[C:31](=[CH:32]\[CH3:33])/[CH2:30][O:29][C:18]1[C:17]([CH3:20])([CH3:21])[O:16][C:4]2=[C:5]3[C:10](=[CH:11][CH:2]=[C:3]2[CH:19]=1)[O:9][C:8](=[O:12])[CH:7]=[C:6]3[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1cc(=O)oc2cc(O)c3c(c12)OC(C)(C)C=C3
Reactant: C/C=C(\C)COC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: C/C=C(\C)COC1=Cc2ccc3oc(=O)cc(CCC)c3c2OC1(C)C
Temperature: 25 °C

Procedure:
5-Hydroxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (Example 8, 107 mg, 0.37 mmol) and caesium carbonate (6 mg, 0.019 mmol) were placed in a flask. A solution of (E)-2-methyl-2-butenyl methyl carbonate (108 mg, 0.75 mmol) in dichloromethane (1 ml) was added. Meanwhile, a solution of (−)-1,2-bis-N-[2′-(diphenylphosphino)benzoyl]-11(S),12(S)-diamino-9,10-dihydro-9,10-ethanoanthracene and then dipalladium tris(dibenzylidineacetone)-chloroform adduct (9.5 mg, 0.025 mmol) in dichloromethane (0.5 mmol) was prepared, then added to the reaction. The suspension was heated to reflux for 8 h, then the yellow solution was allowed to cool to room temperature. After adsorption onto silica (500 mg), and elution with heptane-ethyl acetate (9:1), the (S)-allylic ether in a 11:1 mixture with its allylic regioisomer, i.e. (E2-methyl-2-butenyl)oxy-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one, was obtained as a yellow oil (132 mg, 100%); enantiomeric excess 94% by chiral HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]=O>>[F:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1/[CH:23]=[C:8]1/[C:9](=[O:15])[C:10]2[C:5]([CH2:6][CH2:7]/1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: O=Cc1ccncc1F
Product: COc1cc2c(cc1OC)C(=O)/C(=C/c1ccncc1F)CC2

Procedure:
The title compound 86 was prepared according to the procedure reported in Example 34.2 with 6,7-dimethoxy-1-tetralone (1.65 g, 8 mmol) and 3-fluoro-4-pyridinecarboxaldehyde (1.0 g, 8 mmol) as reactants. White solid. (Yield 2.24 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25][C:26]([F:36])([F:35])C1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][C:20]([C:26]([F:36])([F:35])[F:25])=[CH:21][CH:22]=3)[C:3]=12
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 23 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 4-trifluoromethylbenzaldehyde instead of 3-methylbenzaldehyde in Step 1. As a slightly modified procedure, in Step 2, the reaction mixture was filtered and following evaporation of the filtrate, purification of (3,5-dichloro-6-phenylpyridazin-4-yl)(4-(trifluoromethyl)phenyl)methanone was carried out by trituration of the solid residue in diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.S(=O)(=O)(O)[OH:45].N>C1(C)C=CC=CC=1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]([NH2:20])=[O:45])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCS(=O)(=O)N1CCC(Nc2nn(COCC[Si](C)(C)C)c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Agent: N
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C(N)=O)ccc23)CC1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 396 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 4 ml of toluene. After cooling to 0° C. using an ice bath, 0.64 ml of 95% sulphuric acid is added and the mixture is stirred at RT for 15 h. It is cooled to 0° C. and neutralized with 9 ml of 7.5M aqueous NH3 solution. The product is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. It is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and MeOH (95/05 by vol.). This gives 174 mg of 5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide (yellow solid). MS (E/I): m/z=514 (M+); 1H NMR: 1.23 (t, J=7.4 Hz, 3H); 1.65 (m, 2H); 2.09 (m, 2H); 2.98 (m, 2H); 3.05 (q, J=7.4 Hz, 2H); 3.62 (m, 2H); 3.81 (m, 1H); 6.09 (d, J=8.3 Hz, 1H); 7.33 (m, 2H); 7.55 (broad s, 1H); 7.68 (m, 1H); 8.17 (broad s, 1H); 8.23 (broad s, 1H); 8.35 (broad d, J=8.8 Hz, 1H); 8.45 (d, J=8.8 Hz, 1H); 12.85 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:17][CH:18]1[CH2:20][CH2:19]1)C.[OH-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[CH:18]1([NH:17][C:6]2[CH:7]=[C:8]([N:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:9]([F:11])=[CH:10][C:5]=2[C:4]([OH:21])=[O:3])[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc(F)c(N2CCCC2)cc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c(N2CCCC2)cc1NC1CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.9 %

Procedure:
To a solution of 4-(pyrrolidin-1-yl)-2-cyclopropylamino-5-fluorobenzoic acid ethyl ester (Example 3e, 3.10 g, 10.4 mmol) in methanol (50 mL) and tetrahydrofuran (20 mL) is added 1N solution of sodium hydroxide (35 mL). The reaction mixture is stirred at 80° C. for 20 hours, cooled to room temperature, and diluted with ethyl acetate. The organic layer is washed with 1N hydrochloric acid, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated to afford the title compound as a solid (2.47 g). MS CI: m/z 263 (M+).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]2[CH2:15][C:16]3([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:17]3[C:18](=[O:19])[C:13]2=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C(Cl)Cl>C(O)(=O)C.C1COCC1.O>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:16]23[N:22]([C:23]([C:25]4[C:26]([CH3:30])=[N:27][O:28][CH:29]=4)=[O:24])[CH2:21][CH2:20][N:17]2[C:18](=[O:19])[C:13]2[N:14]([C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)[CH2:15]3)=[CH:36][CH:35]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CO[Si](C)(C)C(C)(C)C)n3CC12c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3ccc(CO)n3CC12c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
8-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10a-(4-chlorophenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (75 mg, 0.14 mmol) was dissolved in a mixture acetic acid/THF/water (3:1:1, 2.5 mL). The solution was stirred at room temperature overnight. After this time there was not anymore starting material (monitored by LCMS). CH2Cl2 was added (20 mL) and washed with saturated aqueous solution of NaHCO3 (3×7 mL). The organic layers were dried (MgSO4), filtered and the filtrate concentrated in vacuo to yield a colourless gum. Purification by flash column chromatography (Biotage SP4, 4 g cartridge, 0-10% MeOH gradient in CH2Cl2) gave 10a-(4-chlorophenyl)-8-(hydroxymethyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a white solid (33 mg, 55% yield). 1H NMR (400 MHz, d6-acetone): δ 2.32 (d, 3H, J 0.5 Hz), 3.75-3.85 (m, 1H), 4.19-4.36 (m, 3H), 4.43-4.47 (d, 1H, J 13.1 Hz), 4.58-4.69 (m, 2H), 6.03 (d, 1H, J 13.2 Hz), 6.09 (d, 1H, J 3.8 Hz), 6.61 (d, 1H, J 3.8 Hz), 7.28-7.32 (m, 2H), 7.50-7.54 (m, 2H), 9.16 (s, 1H). ESI-MI m/z [M+H]+ 427.2.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1)[NH2:2].[C:25](Cl)(=[O:27])[CH3:26].Cl>N1C=CC=CC=1>[C:9]1([C:8]2[C:3]([NH:1][NH:2][C:25](=[O:27])[CH3:26])=[N:4][C:5]([C:21]([F:24])([F:23])[F:22])=[N:6][C:7]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
4-Hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.7 g, 2.1 mmol) (synthesized according to the procedure described in example 21) in pyridine (10 ml) was added acetylchloride (0.17 g, 2.2 mmol) dropwise at 20° C. under stirring for 10 minutes. After 30 minutes of stirring, the reaction mixture was poured onto ice-water mixture, acidified to pH 4 using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to furnish the title compound (0.2 g, 25.4%, HPLC purity 99.4%), mp: 113-116° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH:16][C:17]1[C:26]([CH3:27])=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[CH:19][C:18]=1[CH3:28]>>[CH2:1]([C:5]1[N:10]=[C:9]([C:11]2[O:13][N:23]=[C:21]([C:20]3[CH:25]=[C:26]([CH3:27])[C:17]([OH:16])=[C:18]([CH3:28])[CH:19]=3)[N:22]=2)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Product: COc1cc(CC(C)C)nc(-c2nc(-c3cc(C)c(O)c(C)c3)no2)c1

Procedure:
The title compound is prepared in analogy to Example 2 starting from 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid and 4,N-dihydroxy-3,5-dimethyl-benzamidine; LC-MS: tR=1.01 min, [M+H]+=354.28; 1H NMR (CDCl3): δ 0.99 (d, J=6.8 Hz, 6H), 2.19-2.28 (m, 1H), 2.35 (s, 6H), 2.78 (d, J=7.5 Hz, 2H), 3.98 (s, 3H), 4.96 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.88 (s, 2H).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH3:11])C=CC=CC=1.[C:24]([CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)#[N:25].C(=O)([O-])O.[Na+]>COC(C)(C)C>[CH3:9][O:10][CH:11]=[C:29]1[CH2:30][CH2:31][CH:26]([C:24]#[N:25])[CH2:27][CH2:28]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CC1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=C1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
9.6 g of triphenyl(methoxymethyl)phosphonium chloride were suspended in 50 ml of t-butyl methyl ether under argon gasification and treated portionwise at -10° C. with 3.39 g of solid potassium t-butylate. After completion of the addition, the mixture was stirred at 0° to 5° C. for a further 30 minutes and then the deep orange, partially heterogeneous mixture was treated dropwise within 10 minutes with a solution of 2.30 g of 4-cyanocyclohexanone in 20 ml of t-butyl methyl ether. In so doing the internal temperature should not exceed 5° C. After completion of the addition, the now yellow-orange mixture was warmed to 25° C. and stirred for a further 2 hours. 50 ml of a 2% sodium hydrogen carbonate solution were subsequently added and the separated aqueous phase was extracted twice with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of saturated sodium chloride solution, dried over potassium carbonate and concentrated. The residual semi-crystalline orange oil was triturated with 400 ml of hexane, cooled to -20° C. and freed from precipitated triphenylphosphine oxide by filtration (rinsing with cold hexane). Low-pressure chromatography (0.4 bar) of the concentrated residue on silica gel using 10% ethyl acetate/petroleum ether as the eluant gave 1.60 g (56%) of 4-(methoxymethylene)cyclohexanecarbonitrile as a colourless oil (purity 97%).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](Cl)=[N:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>CN(C=O)C>[CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[N:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Solvent: CN(C)C=O
Product: Cn1c(=NC(C)(C)CO)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Yield: 50.6 %

Procedure:
A solution of 3-Benzyl-2-(biphenyl-4-ylmethyl)-6-chloro-5-methyl-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (9.5 mg, 0.022 mmol) and 2-amino-2-methyl-1-propanol (21 μL, 0.22 mmol) in DMF (2 mL) is heated at 110° C. overnight. The reaction mixture is then purified by chromatography to give 5.5 mg product (Yield: 52%). MS (FAB) m/z 494.4 [M+H]+.