Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([N:32]([CH2:40][CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:40]([N:32]([CH2:30][CH3:31])[C:33]1[CH:34]=[C:35]([NH:39][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=1)[CH3:41]
Reactant: CCN(CC)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc(NC(=O)c2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and crystallised from acetone to give the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.N[C:12]1[C:13](C)=[CH:14]C=[CH:16][CH:17]=1.Cl.C[N:21](C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:13]1([CH3:14])[C:3]([C:8]([NH2:21])=[O:10])=[CH:2][CH:16]=[CH:17][CH:12]=1.[NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccccc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: Nc1nccnc1C(=O)O
Solvent: ClCCl
Product: Cc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminopyrazine carboxylic acid (5.0 g, 35.94 mmol), methylene chloride (110 mL), 4-dimethylaminopyridine (10.98 g, 89.85 mmol), o-toluidine (4.22 mL, 39.53 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.27 g, 43.13 mmol) was stirred overnight at ambient temperature. The solvent was removed and the residue was diluted with ethyl acetate. This organic phase was extracted with 1N lithium chloride (LiCl), water, and brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (2.75×4 inches) with elution proceeding as follows: hexane (300 mL), nil; 20% ethyl acetate/hexane (500 mL), unweighed recovered o-toluidine; 20% ethyl acetate/hexane (1000 mL) and 30% ethyl acetate/hexane (2000 mL), 4.79 g (58%) of 3-aminopyrazine-2-carboxylic acid o-toluamide as a yellow crystalline solid.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][N:3]1[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:42][CH2:43][N:44]([C:20]([C@H:17]2[CH2:18][CH2:19][C@H:14]([CH2:13][N:3]3[CH2:4][CH2:5][C:6]4[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=4[NH:8][C:2]3=[O:1])[CH2:15][CH2:16]2)=[O:22])[CH2:45][CH2:46]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2ccccc2CCN1C[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2CCN1C[C@H]1CC[C@H](C(=O)N2CCN(c3ccccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of trans-4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexanecarboxylic acid (52 mg, 0.17 mmol) in dry DCM (2 mL) was added CDI (50 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 2 h, then 1-Pyridin-2-yl-piperazine (44 μL, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. Then solvent was removed under reduced pressure and crude was purified by crystallization from acetonitrile.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21].O>CN(C)C=O>[CH3:5][O:6][C:7](=[O:30])[C@@H:8]1[CH2:12][C@@H:11]([N:1]=[N+:2]=[N-:3])[CH2:10][N:9]1[C:18](=[O:29])[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
Sodium azide (675 mg) was added to a solution of 1-(N-tert-butoxycarbonyl-N-methylglycyl)-cis-4-methanesulfonyloxy-L-proline methyl ester (B, 0.82 g) in N,N-dimethylformamide (10 mL)-water (1 mL). After stirring at 70° C. for 3 hr, the solvents were removed in vacuo, and the residue was diluted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (0.75 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([P:3](=[O:9])([CH:7]=[CH2:8])[CH:4]([CH3:6])[CH3:5])=[CH2:2].C1COCC1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([N:22]1[CH2:8][CH2:7][P:3](=[O:9])([CH:4]([CH3:6])[CH3:5])[CH2:1][CH2:2]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=CP(=O)(C=C)C(C)C
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)P1(=O)CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A 20 L four-necked round bottom flask fitted with an overhead stirrer and reflux condenser, flame dried and cooled in a stream of nitrogen, was charged with the product of Step 1 (250 g, 1734 mmol), THF (2500 mL), water (2500 mL) and benzyl amine (297.3 g, 2774 mmol). The reaction mixture was heated at 85° C. for 16 h. After completion, THF was removed under reduced pressure. The aqueous layer was extracted with ether to remove the excess of benzyl amine and later with dichloromethane (2×2500 mL). The combined dichloromethane layers were washed with brine (2×1000 mL), dried over sodium sulfate and concentrated to give 1-benzyl-4-(propan-2-yl)-1,4-azaphosphinane 4-oxide (273 g, 63%) as brown oil.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][C@H:13]1[CH2:17][CH2:16][CH2:15][NH:14]1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:12][C@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([C:28]([F:29])([F:31])[F:30])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 82 °C
Yield: 100.1 %

Procedure:
To a solution of (S)-2-methylpyrrolidine tosylate (10.6 g, 41.2 mmol) in acetonitrile (85 mL) was added 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (6.6 g, 31.7 mmol) dropwise and followed by triethylamine (11.0 mL, 79.3 mmol) dropwise. The reaction was heated at 82° C. for 16 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with 1N HCl, then dried over Na2SO4 and concentrated in vacuo to yield (S)-2-methyl-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (8.7 g, quantitative yield). LC/MS m/z 275.3 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[N:32]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C@@H:42]([C:54]([OH:56])=O)[CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)=[O:40])[CH2:35][CH2:34]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1.C(N(C(C)C)C(C)C)C.[O:70]1[CH2:75][CH2:74][CH:73]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1>CN(C=O)C>[O:25]=[C:26]1[N:32]([CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C@H:42]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)[C:54](=[O:56])[N:79]3[CH2:78][CH2:77][N:76]([CH:73]4[CH2:74][CH2:75][O:70][CH2:71][CH2:72]4)[CH2:81][CH2:80]3)=[O:40])[CH2:37][CH2:38]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 3 h

Procedure:
84 mg (0.22 mmol) HATU was added at RT under nitrogen to a solution of 100 mg (0.20 m mol) (R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 110 μL (0.64 mmol) ethyldiisopropylamine and 59 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine (used as the bis-hydrochloride salt) in 5 mL DMF and the mixture was stirred for 3 h. The reaction mixture was evaporated down i.vac. at 50° C. and the crude product was purified by HPLC-MS; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])(C(C)(C)C)(C)C.[NH3:37].C(O)C.Cl>>[OH:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([NH2:37])=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: N
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(N)=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (1.0 g) is reacted with ammonia and hydrolysed with ethanol/HCl following the procedure outlined in example to give the title compound (147 mg). Melting point: 233-235° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.36 (1H, s); 5.45-5.2 (2H, broad d); 3.25 (1H, m). MS: Calculated: 399.6. Found 399.3.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].CN(C)C=O.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)NCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A solution of N-acetylethanolamine (10.0 g, 6.79 ml, 97 mmol) in a mixture of anhydrous tetrahydrofuran (100 ml) and dimethylformamide (10 ml) was added to a stirred suspension of 80% sodium hydride in oil dispersion (2.90 g, 97 mmol) in dry tetrahydrofuran (140 ml), under nitrogen, at room temperature. After 1 hour, the reaction mixture was heated to 40°-50° C. and then, after a further 0.5 hour, cooled to ice-bath temperature. Next, benzyl bromide (13.8 ml, 116 mmol) was added and the resulting suspension stirred at room temperature for 18 hours, before being cautiously quenched with water (400 ml). The resulting mixture was extracted with ethyl acetate (2×300 ml) and the combined extracts washed with water (200 ml), dried (Na2SO4) and evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water, then the organic phase washed thrice with water, dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with a solvent gradient of methanol:ethyl acetate (0:100 to 10:90), to give the required product (7.8 g) as an oil. Rf 0.21 (SS 17). LRMS: m/z 194.3 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[C:5]([CH3:13])=[CH:4][C:3]1=[O:14].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>COC(O)C>[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:12][C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:13])=[CH:4][C:3](=[O:14])[N:2]3[CH3:1])=[CH:7][CH:8]=2)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(=O)n(C)c2cc(O)ccc12
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Agent: COC(C)O
Product: Cc1cc(=O)n(C)c2cc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)ccc12
Yield: 67 %

Procedure:
In a manner analogous to that described in Example 10, by the reaction of 1,4-dimethyl-7-hydroxy-2-oxo-1,2-dihydroquinoline with 3-(4-benzamidopiperidino)-propyl chloride in methoxyethanol, there is obtained, in a yield of 67% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1,4-dimethyl-2-oxo-1,2-dihydroquinoline; m.p. 193°-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[C:14](Cl)(Cl)=[S:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([N:6]=[C:14]=[S:15])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(N=C=S)cc(OC)c1OC

Procedure:
A mixture of 3,4,5-trimethoxyaniline (440 mg; 2.4 mmol) in toluene (20 ml), thiophosgene (300 mg; 2.5 mmol) and triethylamine (500 mg; 5 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trimethoxyphenylisothiocyanate. To the crude product was added 3-[4-(4-chlorophenyl)-1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (40 ml) and refluxed for 16 h. The solvent was evaporated and the residue resuspended in ethyl acetate filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 200 mg of the title compound. M.p. 172°-173° C. MS (70 eV): m/z 479 (M+, 0.1%), 254 (55), 225 (100), 209 (80), 182 (32).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH:23]1([NH2:26])[CH2:25][CH2:24]1.O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][CH:23]1[CH2:25][CH2:24]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
15.6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxy-acrylate are dissolved in 50 ml of ethanol, and 2.75 g of cyclopropylamine are added dropwise, while cooling. The mixture is stirred at room temperature for 1 hour, 50 ml of water are added, while cooling with ice, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 14.1 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-cyclopropylamino-acrylate of melting point 106°-107° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ccc(N3CCOCC3)cc21
Product: CC1c2cc(N3CCOCC3)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: COCCOC.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[N:32]1([C:37]([C:39]2[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=2)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]1>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.O>[CH:13]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[N:30]=[CH:29][C:28]([C:42]4[CH:41]=[CH:40][C:39]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36]5)=[O:38])=[CH:44][CH:43]=4)=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
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: O
Solvent: COCCOC
Product: O=C(c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)cc1)N1CCCC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 475.6 %

Procedure:
1,2-dimethoxyethane (3.0 ml) and aqueous 2 N sodium carbonate solution (1.0 ml) were added to 2-(1-cyclopentylpiperidin-4-yloxy)-5-bromopyrimidine (176 mg, 0.54 mmol), and then 4-(pyrrolidin-1-ylcarbonyl)phenylboronic acid (142 mg, 0.065 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol) were added thereto and stirred in a nitrogen atmosphere at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, and water was added to it and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (C-200, chloroform:methanol=10:1) to obtain the entitled compound (130 mg, 57%).
Reaction SMILES: [C:1]12([O:18][CH2:17][CH2:16][O:15]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([C:11](OC)=[O:12])[CH2:2]2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]12([O:15][CH2:16][CH2:17][O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[O:12])[CH2:2]2
Reactant: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a stirred solution of (R)-methyl 3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carboxylate (4.7 g, 18.93 mmol) in toluene (50 mL) and DCM (12.50 mL) to these solution of DIBAL-H (22.72 mL, 22.72 mmol) was added drop-wise at −78° C. under argon, and the mixture was stirred for 2 h at this temperature. Reaction mixture was quenched with aqueous NH4Cl solution at −78° C. and allowed to RT, filtered through celite, diluted with water (25 mL) and extracted with DCM (2×25 mL), dried over Na2SO4, filtered and concentrated to get the title compound (4.1 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[N:25]1(C(OC(C)(C)C)=O)[CH2:30][CH2:29][CH2:28][C@H:27]2[CH2:31][NH:32][CH2:33][C@@H:26]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:16])[N:32]3[CH2:31][C@H:27]4[C@H:26]([NH:25][CH2:30][CH2:29][CH2:28]4)[CH2:33]3)[C:9]2=[O:17])=[CH:19][CH:20]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]2CNC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1C[C@@H]2CCCN[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D) (0.331 g, 1 mmol) and (4aS,7aS)-tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (Example 50B) (0.226 g, 1 mmol) in methylene chloride (20 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1 mmol) and diisopropylethylamine (0.45 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with methylene chloride, and then washed with 1 N HCl, water, 1 N NaOH, and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel chromatography eluting with ethyl acetate to yield the t-butoxycarbonyl-protected title compound. That material was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (2 mL) for 1 hour at room temperature. The reaction mixture was concentrated and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic layer was separated, dried over MgSO4 and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.35 (m, 4H), 7.00 (m, 4H), 4.25 (dd, 1H), 3.96 (t, J=16.78 Hz, 1H), 3.47 (m, 7H), 3.00 (m, 1H), 2.78 (m, 2H), 2.63 (m, 1H), 2.27 (m, 1H), 1.72 (m, 2H) 1.45 (m, 2H); MS (ESI+) m/z 440 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH:20]([F:32])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:20]([F:32])[F:19])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OCC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS1097730-45-4, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=445.2 [M+H]+.
Reaction SMILES: FS([O-])(=O)=O.Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18].[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)(C)C>[Cl:12][C:11]1[C:7](=[C:20]([C:19]#[N:23])[C:21]#[N:22])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Reactant: N#CCC#N
Agent: O=S(=O)([O-])F
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Cl)C(=C(C#N)C#N)N(C)S1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (7.5 g, 0.022 mole) was dissolved in 75 ml of isopropanol. Malononitrile (1.5 g, 0.023 mol) was added the mixture stirred for 30 min. The yellow solid was collected and washed with isopropanol to yield 2.6 g (44%) of product, mp 134-136. Analysis calculated for C10H8ClN3O2S2 : C 44.51; H, 3.00; Cl, 13.16; N, 15.57; S, 11.90. Found: C, 44.34; H, 2.82; Cl, 12.60; N, 14.82; S, 11.42.