Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.O=[C:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:15]#[N:16].[Cl-].[Ca+2].[Cl-]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: N#CC1CCCC1=O
Reactant: Nc1ccc(Cl)cc1
Agent: [Ca+2]
Agent: [Cl-]
Product: N#CC1=C(Nc2ccc(Cl)cc2)CCC1

Procedure:
4-Chloro-aniline (Aldrich Chemicals) (2.6 g, 20 mmol), cyanoketone (Example 11) (2.2 g, 20 mmol), calcium chloride (2.5 g, 23 mmol) and T.H.F. (30 ml) were heated under reflux for 19 hours. After being allowed to cool, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (160° C., 0.3 mm Hg) gave the product as white crystals.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH2:10][NH:11][C:12](=[O:23])OC2C=CC([N+]([O-])=O)=CC=2)[O:6][CH2:5][CH2:4][O:3]1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:12]([NH:11][CH2:10][C:9]2[CH:24]=[CH:25][CH:26]=[C:7]([C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)[CH:8]=2)=[O:23])=[CH:30][CH:29]=1
Reactant: CC1(c2cccc(CNC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)OCCO1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cccc(CNC(=O)Nc3ccc(Cl)cc3)c2)OCCO1
Temperature: 25 °C
Yield: 62 %

Procedure:
4-Nitrophenyl-N-benzylcarbamate 21 (267 mg, 0.767 mmol) was added to a solution of 4-chloroaniline (97 mg, 0.767 mmol) and triethylamine in dichloromethane (5 mL). The mixture was stirred at room temperature until starting materials were consumed. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with aq. NaOH, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated The residue was purified by column chromatography eluting with methanol/chloroform to give 22 (165 mg, 71%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 3.71 (t, J=6.8 Hz, 2H), 3.99 (t, J=6.8 Hz, 2H), 4.36 (d, J=5.6 Hz, 2H), 6.78 (s, 1H), 7.16-7.18 (m, 4H), 7.23-7.26 (m, 1H), 7.35 (d, J=5.6 Hz, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1, 92 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) was added, the mixture was flushed with argon, heated to 100° C. in a pressure safe vial, then Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) was added. The RM was stirred under argon at 80-90° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a beige crystalline powder. HPLC (Condition 4) tR=5.02 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, tR=10.32 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=1.00 Hz, 1H) 3.21 (m, J=6.60 Hz, 2H) 3.32-3.42 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.09 (d, J=1.95 Hz, 1H) 8.76-8.80 (m, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([CH3:16])[C:13]([OH:15])=O)[C:7]1=[O:17])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:49][O:50][C:51](=[O:85])[NH:52][CH:53]([C:57]([N:59]1[CH2:63][CH2:62][CH2:61][CH:60]1[C:64]1[NH:65][C:66]([C:69]2[CH:74]=[CH:73][C:72]([C:75]3[CH:80]=[CH:79][C:78]([C:81](=[O:84])[CH2:82][NH2:83])=[CH:77][CH:76]=3)=[CH:71][CH:70]=2)=[CH:67][N:68]=1)=[O:58])[CH:54]([CH3:56])[CH3:55]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]([C:13](=[O:15])[NH:83][CH2:82][C:81]([C:78]2[CH:79]=[CH:80][C:75]([C:72]3[CH:71]=[CH:70][C:69]([C:66]4[NH:65][C:64]([CH:60]5[CH2:61][CH2:62][CH2:63][N:59]5[C:57](=[O:58])[CH:53]([NH:52][C:51]([O:50][CH3:49])=[O:85])[CH:54]([CH3:56])[CH3:55])=[N:68][CH:67]=4)=[CH:74][CH:73]=3)=[CH:76][CH:77]=2)=[O:84])[CH3:16])[C:7]1=[O:17]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(C(=O)CN)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC1CCCN(C(C)C(=O)O)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)NC1CCCN(C(C)C(=O)NCC(=O)c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)C1=O
Yield: 100 %

Procedure:
A solution of 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid (48.5 mg, 0.20 mmol), HATU (91 mg, 0.24 mmol), and 4-methylmorpholine (109 μL, 0.99 mmol) in dimethylformamide (5 mL) was stirred at ambient temperature for 5 minutes. [1-(2-{5-[4′-(2-Amino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (100 mg, 0.20 mmol) was added to the reaction mixture. After 40 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane followed by 30% methanol in DCM. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide (1-{1-[2-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-2-oxo-ethylcarbamoyl]-ethyl}-2-oxo-piperidin-3-yl)-carbamic acid methyl ester (149 mg, 0.20 mmol, 99%). C38H47N7O8 calculated 729.4 observed [M+1]+ 730.6; rt=1.78 min.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH2:31][CH2:32][CH2:33][OH:34]>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:32][CH2:33][OH:34])[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: NCCO
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCNCCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 2-aminoethanol following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 8.70 (s, 2H), 7.86 (d, 1H), 7.01 (d, 1H), 4.70 (s, 1H), 4.52 (br, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 3.43 (t, 2H), 2.58 (t, 2H), 2.53 (m, 2H), 1.74 (m, 2H), 1.48-1.28 (m, 6H) [NH's not seen]; MS (ESI): 495.3.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: Cc1ccc(F)c(-c2nc(C(=O)O)c(NC(=O)OC(C)(C)C)s2)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)c(N)s2)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxylic acid (Intermediate 133) gave 292. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.82 (s, 1H), 7.44 (s, 2H), 7.26-7.17 (m, 2H), 4.86 (dd, J=10.2, 3.8 Hz, 1H), 4.54-4.36 (m, 1H), 4.34-4.18 (m, 1H), 4.15-3.96 (m, 1H), 3.77 (s, 3H), 2.35 (s, 3H), 2.14-2.03 (m, 1H), 1.88-1.65 (m, 4H). LCMS (ES+) m/z 463 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[C:15]([C@H:19]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49]([NH:51][C@:52]2([C:57](=[O:66])[NH:58][S:59]([C:62]3([CH3:65])[CH2:64][CH2:63]3)(=[O:61])=[O:60])[CH2:54][C@H:53]2[CH:55]=[CH2:56])=[O:50])[O:41][C:31]2=[N:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39](O)=[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[CH2:67][C@H:23]2[O:22][C:21](=[O:68])[NH:20]1)([CH3:18])([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:15]([C@H:19]1[C:46](=[O:47])[N:45]2[CH2:48][C@@H:42]([CH2:43][C@H:44]2[C:49](=[O:50])[NH:51][C@:52]2([C:57](=[O:66])[NH:58][S:59]([C:62]3([CH3:65])[CH2:63][CH2:64]3)(=[O:60])=[O:61])[CH2:54][C@H:53]2[CH:55]=[CH2:56])[O:41][C:31]2=[N:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=3[C:39]([O:1][CH2:2][C@H:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)=[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[CH2:67][C@H:23]2[O:22][C:21](=[O:68])[NH:20]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1(C)CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC[C@H]1CCN(C(=O)OC(C)(C)C)C1)O2)C(=O)NS(=O)(=O)C1(C)CC1

Procedure:
The title compound was prepared using the same method as described in Example 75, using the tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate and (1aR,5S,8S,10R,22aR)-5-tert-butyl-N-[(1R,2S)-2-ethenyl-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-17-hydroxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxamide (Example 120). The method was slightly modified as triphenylphosphine was used instead of trimethylphosphine and the reaction was done at a 0.3 M concentration LRMS (ES+) m/z 949.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([OH:16])[CH:9]=2.[I-].[N:24]1([C:34](N2C=C[N+](C)=C2)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[CH2:4][C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][CH:11]=[C:10]([O:16][C:34]([N:24]1[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][CH2:25]1)=[O:35])[CH:9]=2
Reactant: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(O)ccc12
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Agent: [I-]
Product: Cc1c(Cc2c(F)cccc2Cl)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)ccc12

Procedure:
The title compound was prepared from 3-(2-chloro-6-fluoro-benzyl)-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z =478 (M+1), Rt: 5.58 min.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[Mg].[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1>>[CH3:13][N:14]([CH3:23])[C:15]1[CH:22]=[CH:21][C:18]([C:19]([C:6]2[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)c1ccc(Cl)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Mg]
Product: CN(C)c1ccc(C(=O)c2ccc([Si](C)(C)C)cc2)cc1

Procedure:
A Grignard reagent prepared from 0.2 mole of 4-trimethylsilylchlorobenzene and 0.2 mole of magnesium was reacted with 0.2 mole of 4-dimethylaminobenzaldehyde. The resulting reactant was subjected to oxidation by the Oppenauer method, to yield 4-dimethylamino-4'-trimethylsilyl benzophenone.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.Cl.N1C=CC=CC=1>O>[CH3:12][C:10]1[CH:11]=[C:3]([OH:2])[CH:4]=[C:5]2[C:9]=1[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(O)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
In a round bottom flask was placed 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (3.9 mmole, 1.01 g) and pyridine hydrochloride (25 g). The flask was then placed in a preheated oil bath set at 190° C. for 45 minutes. This solution was cooled to room temperature. The resulting solidified material was dissolved in water (200 mL). The pH was adjusted to approximately 10.3, which resulted in a precipitate. The insoluble material was collected by filtration, rinsed with water to afford 0.781 g (82%) of the title compound: mass spectrum (ion spray): m/z=245 (M+1); 1H NMR (DMSOd6): 10.40 (s, 1H), 8.45 (s, 1H), 6.93 (s, 1H), 6.68 (s, 1H), 6.40 (s, 1H), 2.90 (m, 2H), 2.60 (m, 1H), 2.36 (s, 3H), 2.26 (s, 3H), 2.08 (m, 2H), 1.90 (m, 2H), 1.70 (m, 2H); Calculated for C15H20N2O: C, 73.74; H, 8.25; N, 11.47. Found: C, 73.76; H, 8.15; N, 11.71.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH2:16]([SH:20])[CH2:17][CH2:18][SH:19]>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[S:20][CH2:16][CH2:17][CH2:18][S:19]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: SCCCS
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc(C2SCCCS2)cc1
Temperature: 0 °C

Procedure:
4-Hydroxybenzaldehyde (46 g, 0.377 mol), recrystallized from benzene, and 1,3-propanedithiol (45 ml, 0.449 mol) were added to dry chloroform. The reaction mixture was stirred at 0° C. and HCl gas was bubbled through the solution for 10 minutes. After the exothermic reaction stopped the solution was refluxed for 10 hours. A white precipitate formed. This was filtered off and the chloroform solution was washed with water three times, dried (MgSo4) and evaporated under reduced pressure to yield a light yellow solid. White needles were obtained after recrystallization from chloroform, MP=151°-152° C. The white precipitate was also recrystallized from chloroform to yield white needles that melted at 151°-152° C. IR and NMR confirmed the two compounds to be identical. Total yield after recrystallization: 99%.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>C(Cl)Cl.C(N(CC)CC)C>[C:11]([CH2:10][CH2:9][N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=1)[C:16]([CH:13]1[CH2:15][CH2:14]1)=[O:17])#[N:12]
Reactant: O=C(Cl)C1CC1
Reactant: N#CCCNc1cccc(I)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCN(C(=O)C1CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
1.0 g of 3-(3-iodo-phenylamino)-propionitrile are dissolved in a mixture of 25 ml of methylene chloride and 0.45 ml of triethylamine and treated dropwise at 0° with a solution of 0.42 g of cyclopropanecarbonyl chloride in 5 ml of methylene chloride. The solution is stirred at room temperature for a further 2 hrs., then poured into ice-water and extracted three times with ethyl acetate. Concentration yields 1.19 g of crude cyclopropanecarboxylic acid (2-cyano-ethyl)-(3-iodo-phenyl)-amide which is used in Example 12av) without further purification. Yield: 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][OH:15])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of DL-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid in a mixture of DMF/DCM 1:5, 1.24 g of imidazole and 1.7 g of tert-butyldimethylsilyl chloride were added. The solution was left stirring at room temperature overnight. The solution was extracted three times with 5% aq. NaHSO4 and the aqueous phases were washed twice with DCM. The organic extracts were dried over anh. sodium sulfate and the solvent evaporated under vacuum to provide 2.1 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([CH:27]1[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1)#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:33]([CH:30]3[CH2:31][CH2:32][CH:27]([C:25]#[N:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: N#CC1CCC(C(=O)O)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(C#N)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4-cyano-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4-cyano-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 484.2 [M+H]+.
Reaction SMILES: [F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].[CH3:14][OH:15]>>[F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:15][CH3:14])=[O:4]
Reactant: CCCC[C@](F)(C(=O)Cl)C(F)(F)F
Reactant: CO
Product: CCCC[C@](F)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 ml of methanol was added 0.17 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl chloride, and this mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was distilled with Kugelrohr under atomspheric pressure, thereby obtaining 0.15 g of methyl (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoate having the physical properties as mentioned hereinbefore.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:16](C(OCC(Cl)(Cl)Cl)=O)[CH2:15][CH:14]4[CH2:25][CH2:26][CH2:27][N:13]4[C:12](=[O:28])[C:11]=3[CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C(OCC)(=O)C>C1COCC1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:16]=[CH:15][C@@H:14]4[CH2:25][CH2:26][CH2:27][N:13]4[C:12](=[O:28])[C:11]=3[CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2CCCN2C(=O)c2cc(-c3ccccc3)ccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2cc(-c3ccccc3)ccc2N=C[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Cd/Pb (0.47 g) couple was added portion wise to a vigorously stirred solution of 135 (0.33 g, 0.7 mmol) in THF (5 mL) and of aq. ammonium acetate (1M, 5 mL). The suspension was allowed to stir at room temperature for 2 hours, then poured into ethyl acetate (200 mL), dried with MgSO4 and filtered. The filtrate was evaporated and the residue purified by flash column chromatography (ethyl acetate) to afford the title compound as colourless oil (0.19 g, 98%): 1H NMR (270 MHz, CDCl3) δ2.0-2.12 (m, 2H); 2.29-2.37 (m, 2H); 3.53-3.63 (m, 1H); 3.76-3.92 (m, 2H); 7.36-7.79 (m, 8H); 8.28 (d, J=2.2 Hz, 1H). 13C NMR (67.8 MHz, CDCl3) δ24.4; 29.8; 46.9; 53.8; 126.9; 127.3; 127.7; 128.0; 128.2; 128.8; 128.9; 129.1; 130.1; 130.5; 139.5; 145.0; 164.5; 165.1. IR (Nujol): cm−1 3000-2800, 1620, 1455, 1377, 1239, 1239, 1014, 990, 761,728, 697. HRMS Calculated for C18H16N2O: 276.1261. Found: 276.1262. [α]25D=+131.4° (c=0.19, CHCl3).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[C:17]4[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:20](=[O:23])[NH:21][CH2:22][C:16]4=[C:15](Cl)[N:14]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+].[F:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:65])[C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[C:51](B3OC(C)(C)C(C)(C)O3)[CH:50]=2)=[CH:43][CH:42]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:14]=[C:15]([C:51]4[CH:50]=[C:49]([CH:54]=[CH:53][C:52]=4[CH3:55])[C:48]([NH:47][C:44]4[CH:45]=[CH:46][C:41]([F:40])=[CH:42][CH:43]=4)=[O:65])[C:16]4[CH2:22][NH:21][C:20](=[O:23])[N:19]([C:24]5[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=5[F:31])[C:17]=4[N:18]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(N3CCCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 49.6 %

Procedure:
To a solution of compound 7-(1,4′-bipiperidin-1′-yl)-5-chloro-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (18 mg, 0.04 mmol) in dioxane (1.5 mL)/water (0.5 mL) were added potassium carbonate (34 mg, 0.25 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 mg, 0.002 mmol) and N-(4-fluorophenyl)-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22 mg, 0.062 mmol).The reaction mixture was bubbled with N2 for 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (13 mg, 51%). LC-MS m/z 656 (M+H)+; 1H-NMR (CD3OD) δ 1.37 (m, 2 H), 1.48 (m, 2 H), 1.60 (m, 4 H), 1.80 (m, 2 H), 2.33 (s, 3 H), 2.56 (m, 5 H), 2.72 (t, 2 H), 4.17 (m, 2 H), 4.46 (m, 2 H),7.12 (m, 4 H), 7.52 (m, 2 H), 7.72 (m, 2 H), 7.82 (s, 1 H), 7.98 (d, 1 H).