Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH:46]=O)=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH2:46][CH:2]=[O:3])=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
After methoxymethyl triphenyl phosphonium chloride (1.04 g, 3.02 mmol) was dissolved in anhydrous THF (9 mL), LiHMDS 1.0M THF solution (3 mL, 3.02 mmol) was added thereto at 0° C., and the mixture was stirred for 15 minutes. 4-Benzyloxy-3,5-difluoro-benzaldehyde (0.50 g, 2.01 mmol) obtained in Step B of Preparation Example 2 was dissolved in anhydrous THF (6 mL), and the solution was added thereto. The mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/5). After the obtained product was dissolved in THF (7.68 mL), 2N HCl (3.84 mL) was added thereto, and the mixture was stirred at 70° C. for 5 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and the purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.107 g, 20%).
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](C1CCCCN1CCCN)C>>[CH3:25][CH:12]1[CH2:11][CH2:10][C:9]2[N:8]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:23][CH:24]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][C:14]=2[CH2:13]1
Reactant: CCC1CCCCN1CCCN
Reactant: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 62 %

Procedure:
Following the general methods as outlined under Example 1, starting from 4-(2-phenyl-4,5,6,7-tetrahydro-1H-indol-1-yl)benzoic acid (Intermediate 7) and 3-(2-ethylpiperidin-1-yl)propan-1-amine, the title compound (8) was isolated as a beige solid in 62% yield (94% purity by HPLC). MS(ESI+): 470.8; MS(ESI−): 468.7.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([OH:14])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:12](=[O:14])[CH2:11][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CC1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)CC1CCc2ccccc2C1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of 3.4 g of 1,2,3,4-tetrahydronaphthalen-2-ylacetic acid in 50 ml of methylene chloride was added 14.1 g of WSC.HCl with stirring at room temperature. Then, 3.6 g of L-proline methyl ester hydrochloride and 2.2 g of triethylamine were added to the solution. The mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.6 g of 1-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-proline methyl ester as a colorless oil.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[CH3:7][C:8]([O:11][C:12]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])([CH3:10])[CH3:9]>>[C:8]([O:11][C:12](=[O:13])[NH:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]([N:5]1[CH2:6][CH:3]([OH:2])[CH2:4]1)=[O:24])([CH3:10])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OC1CNC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CC(O)C1

Procedure:
3-Hydroxyazetidine hydrochloride (J. Chem. Soc., Chem. Commun. 1968, p93, 27 mmol) and N-t-Boc-L-phenylalanine (27 mmol) were coupled according to Procedure A giving the title substance as a colorless foam (8.15 g, 93%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccccc1C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (8,7 g) and 2,4-pentanedione (5,01 g) in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over night at 20°? C. The solvent was evaporated and the residue was distilled in vacuo, bp 110° C./1.5 mbar. Yield 5.3 g (41 %).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15](O)=[O:16])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].O.[NH2:21][NH2:22]>C(O)C>[C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH:12]3[CH:13]([C:15](=[O:16])[NH:21][N:22]=2)[CH2:14]3)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: NN
Reactant: CCC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 81.8 %

Procedure:
1.0 g (3.8 millimoles) of cis-2-(p-propionylaminobenzoyl)-cyclopropanecarboxylic acid, 0.22 g (4.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 5 hours. After filtering off the product at 25° C. and drying it under reduced pressure at 50° C., 0.8 g (81% of theory) of 2-(p-propionylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 268°-270° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:26](C(OC(C)(C)C)=O)[C@@H:27]([C:32](O)=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C@@H:27]([C:32]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[CH:24][CH:25]=1)=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 107.6 %

Procedure:
Following the procedures of Preparation Ic, a reaction mixture comprising (i) 910 mg (1.57 mmol) of H-Gly-L-Arg-pNA.2H-TFA, (ii) 363 mg (1.57 mmol) of Boc-D-Leu-OH, (iii) 1.2 ml of DIEA and (iv) 695 mg (1.57 mmol) of Bop is reacted in DMF and the reaction mixture is kept at RT for 2 h, with stirring. After evaporation to dryness under vacuum, the evaporation residue is chromatographed on silica gel using a CHCl3 /MeOH/AcOH gradient (20/3/1 to 10/3/1 v/v) as the eluent. The homogeneous fractions collected are pooled and the eluent is evaporated off. Lyophilization gives 785 mg (yield: 80%) of the expected product in pure form.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.[CH:31](=[O:33])[CH3:32]>C(OCC)C.O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:10]([CH:31]([OH:33])[CH3:32])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(NC(=O)OC(C)(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 20 °C
Yield: 85.1 %

Procedure:
3.3 g (0.01 mol) (4-tert.butoxycarbonylamino-3-bromophenyl)carbamic acid-tert.-butyl ester are dissolved in 200 ml diethyl ether under argon. Then first 20 ml of a 1.6 molar methyl lithium solution are added at −25° C. and then 16 ml of a 1.6 molar tert.-butyl lithium solution are added. After one hour 1.2 ml (0.02 mol) of acetaldehyde are added and the reaction mixture is slowly heated to 20° C. After halting the reaction the reaction mixture is hydrolyzed with water, the organic phase is extracted with dilute sodium hydroxide and then dried with magnesium sulfate. The solvent is distilled off in a rotary evaporator and the residue is purified with petroleum ether/acetic acid ethyl ester (8:2). 3.0 g (85% of theoretical) of (4-tert.-butoxycarbonylamino-3-(1-hydroxyethyl)phenyl)carbamic acid-tert.-butyl ester having a melting point of 189° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=1.[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)C.C(OCC)(=O)C>[CH3:17][C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)([CH3:15])[CH3:16]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(F)cnc1NCc1ccc(C(C)(C)C)cc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl 2-chloro-5-fluoro-3-pyridinecarboxylate (0.490 g, 2.41 mmol) in ethanol (10.0 mL) was treated with 4-tert-butylbenzylamine (0.450 mL, 2.55 mmol). The mixture was heated to 150° C. for 0.5 h and then to 160° C. for 20 min. in a Biotage Initiator microwave synthesizer. The solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography (20-40% ethyl acetate in hexanes) afforded a mixture of the title compound and starting material as a clear yellow oil (0.326 g, 41%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.39 (d, J=3.0 Hz, 1H), 8.20 (d, J=3.3 Hz, 1H), 8.14 (t, J=5.1 Hz, 1H), 7.91 (dd, J=6.9, 3.2 Hz, 2H), 7.89 (dd, J=8.1, 3.0 Hz, 2H), 4.69 (d, J=5.3 Hz, 2H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.32 (s, 9H). MS(ES+) m/e 331 [M+H]+.
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[C:36]([C:50]([O:52]C)=O)=[N:37][N:38]([C:42]3[CH:43]=[N:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=3)[C:39](=[O:41])[CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:50]([C:36]1[C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]2)=[CH:40][C:39](=[O:41])[N:38]([C:42]2[CH:43]=[N:44][C:45]([C:48]#[N:49])=[CH:46][CH:47]=2)[N:37]=1)(=[O:52])[NH2:11]
Reactant: COC(=O)c1nn(-c2ccc(C#N)nc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)nc3)nc2C(N)=O)CC1
Yield: 77 %

Procedure:
tert-Butyl 4-(3-carbamoyl-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 77% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(6-cyanopyridin-3-yl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 30). MS (ESI) 441 (M+H).
Reaction SMILES: CO[C:3](=[O:11])[CH:4]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)[CH3:5].O.[NH2:13][NH2:14]>C(O)CCC>[N:6]1([CH:4]([CH3:5])[C:3]([NH:13][NH2:14])=[O:11])[CH:10]=[N:9][CH:8]=[N:7]1
Reactant: COC(=O)C(C)n1cncn1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CC(C(=O)NN)n1cncn1
Yield: 91 %

Procedure:
As described for example 112a, (rac.)-2-[1,2,4]triazol-1-yl-propionic acid methyl ester in butanol was reacted with hydrazine hydrate (1.2 equivalents) at rt for 16 h. The mixture was concentrated and triturated with toluene to afford the title compound as a white solid (yield: 91%). MS: m/e=155.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: Cc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 52.6 %

Procedure:
Prepared according to Procedure C using Intermediate 2j (200 mg, 0.626 mmol), 6-mercaptopurine monohydrate (93 mg, 0.546 mmol), K2CO3 (95 mg, 0.689 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 125 mg of an off-white solid (46%), mp 213.9° C. 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.63 (d, J=8.2 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.49 (d, J=6.9 Hz, 1H); 7.24-7.41 (m, 3H); 4.32-4.45 (m, 2H); 2.14 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.2, 154.2, 151.5, 149.7, 149.6, 143.5, 136.1, 135.9, 135.1, 133.2, 131.3, 130.3, 130.0, 129.9, 129.1, 127.6, 127.1, 117.8, 32.4, 17.5. MS (ES): m/z 438.0 (M+). Anal. calcd. for C21H15ClN6OS: C, 58.00; H, 3.48; Cl, 8.15; N, 19.32; S, 7.37. Found: C, 58.05; H, 3.38; Cl, 8.89; N, 18.38; S, 7.00.
Reaction SMILES: [CH2:1]([O:7][N:8]=[C:9]([C:15](=[O:17])[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:21])(=O)=O>C(O)(=O)C>[CH2:1]([O:7][N:8]=[C:9]([C:15](=[O:17])[CH2:16][Cl:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCON=C(C(=O)CCl)C(=O)OCC
Yield: 80.2 %

Procedure:
Ethyl 2-n-hexyloxyimino-3-oxobutyrate (syn isomer, 60.7 g.), acetic acid (61 ml.) and sulfuryl chloride (34.7 g.) were treated in a similar manner to that of Example F-(2) to give ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.).
Reaction SMILES: [OH-].[CH2:2]([N+:9](C)(C)C)[C:3]1C=CC=C[CH:4]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:18]([NH:20][CH2:21][C:22]1[NH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)=[O:19].C(#N)C=C>C(Cl)Cl>[C:2]([CH2:3][CH2:4][N:23]1[C:24]([CH3:27])=[CH:25][CH:26]=[C:22]1[CH2:21][NH:20][C:18](=[O:19])[C:17]1[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:15]([O:14][CH3:13])[CH:16]=1)#[N:9]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: COc1ccc(C(=O)NCc2ccc(C)[nH]2)cc1OC
Agent: [OH-]
Solvent: C=CC#N
Solvent: ClCCl
Product: COc1ccc(C(=O)NCc2ccc(C)n2CCC#N)cc1OC
Reaction time: 0.5 h

Procedure:
3 ml of benzyltrimethyl-ammonium hydroxide (40% strength solution in methanol) are added dropwise to 5.1 g (0.019 mol) of 2-(3,4-dimethoxybenzoylamino-methyl)-5-methyl-pyrrole (compare Example 16) and 15 ml (0.23 mol) of acrylonitrile, while cooling. After 30 minutes, methylene chloride is added, the mixture is filtered, water is added, and the methylene chloride phase is separated off and concentrated. Recrystallisation from ethyl acetate gives 4.3 g of product of melting point: 175° to 176° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27.7 %

Procedure:
4-Amino-1-N-Boc piperidine (1.80 g, 8.9 mmol) was dissolved in CH2Cl2 and 4-chlorobenzylbromide (1.84 g, 8.9 mmol) and triethylamine (1.25 mL, 8.9 mmol) were added. The solution was allowed to stir for 14 h at room temperature and evaporated in vacuo and partitioned between ether/1N NaOH. The aqueous layer was removed and the ether was washed with brine and dried over MgSO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (5% methanol/95% methylene chloride) to yield the title compound (0.800 g, 27%). 1H-NMR (CDCl3): δ 1.26 (m, 1H), 1.44 (s, 9H), 1.83 (d, 2H), 2.63 (t, 1H), 2.78 (t, 2H), 3.46 (s, 2H), 3.78 (s, 2H), 4.00 (bs, 2H), 7.26 (bs, 4H). ESI-MS m/z: 325.1 (M+1), retention time 1.86.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2[CH:3]=[CH:2][N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccn3nccc3n2)cc1
Yield: 67.5 %

Procedure:
A mixture of 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.5, step 2) (1.06 g, 4.0 mmol), triethylamine (0.84 mL), and 5% Pd—C (0.1 g) in EtOH (40 mL) was stirred in an atmosphere of hydrogen for 1.5 h. The catalyst was filtered off, the solution was evaporated in vacuo and the residue was crystallized from EtOAc/cyclohexane to give 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (0.62 g, 67%) as a pale-yellow solid. MS (ISP) 230.4 [(M+H)+]; mp 178-180° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]#[N:14])[C:7]2[CH:8]=[N:9][N:10]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C#N)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
Sodium hydride (0.108 g, 4.50 mmol) was added to a stirred solution of 6-bromo-1H-indazole-4-carbonitrile (0.5 g, 2.252 mmol) in N,N-dimethylformamide (10 ml) at room temperature. The mixture was stirred at room temperature for 10 mins when p-toluenesulphonyl chloride (0.558 g, 2.93 mmol) was then added. The pale yellow suspension was stirred for 20 mins at room temperature. The mixture was poured into stirring water (100 ml) and the precipitated product collected by filtration. The cream coloured solid was dried in vacuo at 65° C. to give the title compound (0.794 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1.[CH3:22]OC(=O)OC.CN(C)C=O>O>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH3:22])[C:10]2=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)OC
Reactant: O=C1NCc2cccnc2N1c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2cccnc2N(c2cccc(C(F)(F)F)c2)C1=O
Yield: 76.3 %

Procedure:
A mixture of 0.5 g 1-(m-trifluoromethylphenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine, 0.8 g of dimethylcarbonate and 10 ml of dimethylformamide was reacted at 160° - 170° C in sealed-tube for 20 hours. After the reaction was finished, the solvent was distilled off from the mixture to leave a residue, to which was added water. This residue was extracted with ether and then dehydrated. The ether solution was applied on a column of alumina, and then eluted with ether. The ether was evaporated from the eluate and left to give 0.4 g of 1-(m-trifluoromethylphenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 122° - 124° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1.CC#N>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 134, 152 mg, 0.34 mmol) in CH2Cl2 (15 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooled by the ice bath, and was then allowed to warm to r.t. then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3 and then brine. The organic solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude product (100 mg) as a beige solid after trituration with diethyl ether. CH3CN (˜3 mL) was then added to the crude product and the resulting slurry was stirred at 50° C. for 4 h. After cooling to r.t. the suspended solid was collected by filtration, washed with CH3CN and dried at 45° C. overnight to give the title compound (72 mg, 42%) as a yellow solid; 1H NMR: 1.68-1.81 (3H, m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H, m), 3.00-3.05 (2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H, s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd), 6.48-6.56 (2H, m), 6.96 (1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z: ES+ MH+ 503.67.