Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]#[CH:20])[C:14]=1[C:21]#[N:22].C(N(CC)CC)C>C(Cl)Cl.O>[CH:12]([C:13]1[CH:17]=[CH:16][N:15]([CH2:18][C:19]#[CH:20])[C:14]=1[C:21]#[N:22])=[O:11]
Reactant: C#CCn1ccc(CO)c1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: C#CCn1ccc(C=O)c1C#N
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
27 ml of a 1M solution of oxalyl chloride in methylene chloride were cooled to -60° C. and 13.5 ml of a 1M solution of dimethyl sulfoxide in methylene chloride were added. After stirring for 5 minutes, a solution of 1.09 g of 3-hydroxymethyl-1-(2-propynyl)-1H-pyrrole-2-carbonitrile in 20 ml of methylene chloride was added, and the temperature was kept at -60° C. for 2 hours. 70 ml of a 1M solution of triethylamine in methylene chloride were added with stirring for 10 minutes at -60° C., and the temperature was allowed to rise to 20° C. 20 ml of water were added, followed by stirring, decanting and concentrating to dryness. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (6-4) to obtain 456 mg of 3-formyl-2-cyano-1-(2-propynyl)-1H-pyrrole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P([N:38]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[NH2:38][C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of the compound (1.2 g) obtained in step 4 in toluene (9 mL) were added DPPA (1.06 mL) and triethylamine (0.68 mL) at room temperature, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled, 8N aqueous sodium hydroxide solution (4.2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and brine and dried, and the solvent was evaporated under reduced pressure to give tert-butyl (3S,4R)-3-amino-4-(3,4-dichlorophenyl)pyrrolidine-1-carboxylate (1.06 g, 96%) as a colorless oil.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:11])[NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCCN(Cc2cccnc2)C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccnc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 41 (4.4 mg, 0.020 mmol) to give a white solid (4.5 mg, 47% yield). Anal. Calcd. for C43H53N5O6S m/z 767.7. found: 768.7 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (br. s., 1H), 8.69 (d, J=4.95 Hz, 1H), 8.11 (d, J=7.70 Hz, 1H), 7.70 (dd, J=7.70, 5.50 Hz, 1H), 7.22 (t, J=7.42 Hz, 4H), 7.19-7.10 (m, 6H), 6.98 (d, J=6.60 Hz, 1H), 6.79 (d, J=6.60 Hz, 1H), 5.35-5.28 (m, 1H), 5.15-5.08 (m, 1H), 4.98 (br. s., 1H), 4.88 (d, J=15.40 Hz, 1H), 4.68-4.57 (m, 1H), 4.44 (d, J=15.40 Hz, 1H), 3.67 (s, 3H), 3.60 (dd, J=15.12, 11.82 Hz, 1H), 3.29-3.10 (m, 2H), 2.84-2.77 (m, 3H), 2.77-2.67 (m, 2H), 2.04-1.97 (m, 2H), 1.90-1.48 (m, 13H), 1.26 (t, J=7.15 Hz, 2H), 1.13 (d, J=13.20 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1.[NH:7]([C:14]1[N:19]=[C:18]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH:28]=O)=[N:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[NH2:31][OH:32].O>CCO>[NH:7]([C:14]1[N:19]=[C:18]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH:28]=[N:31][OH:32])=[N:22][CH:21]=2)[CH:17]=[CH:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=NO

Procedure:
Pyridine (283 μl, 3.50 mmol) was added to a solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 250 mg, 0.814 mmol) and hydroxylamine.hydrochloride (283 mg, 4.07 mmol) in EtOH (8 ml) and the reaction mixture heated at reflux for 1 hr. The mixture was allowed to cool, water (10 ml) was added and the EtOH was removed by evaporation. Further water (10 ml) was added to the aqueous residue and the precipitated solid was collected by filtration, washed with water and dried to give the title compound as a 9:1 mixture of E and Z isomers (142 mg, 54%) as a white solid. NMR: Major isomer: 1.47 (d, 6H), 5.70 (m, 1H), 6.95 (t, 1H), 7.10 (d, 1H), 7.31 (t, 2H), 7.60 (s,1 H) 7.69 (d, 2H), 8.25 (s, 1H), 8.50 (d, 1H), 9.50 (s, 1H), 11.70 (s, 1 H); Minor isomer: 1.47 (d,6H), 5.70 (m, 1H), 6.95 (t, 1H), 7.19 (d, 1H), 7.31 (t, 2H), 7.69 (d, 2H), 7.78 (s, 1H), 8.10 (s, 1H), 8.52 (d, 1H), 9.57 (s, 1H), 13.89 (s, 1 H); m/z 323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21](SC)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:30])[F:29])[CH:4]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[C:18]4[S:22][C:21]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]5)=[N:20][C:19]4=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:28]([F:31])([F:29])[F:30])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(C=C4SC(SC)=NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: O=C(O)C1CCNCC1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCC(C(=O)O)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
1-{5-[1-(4-M ethoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid was prepared from 5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:12]1[CH:16]=[N:15][C:14]([C:17]([O:19]C)=[O:18])=[N:13]1.ClC1C=C(N2C=NC(C(O)=O)=N2)C=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[N:13]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: COC(=O)c1nc[nH]n1
Agent: O=C(O)c1ncn(-c2cccc(Cl)c2)n1
Product: Cc1ccc(-n2cnc(C(=O)O)n2)cc1F

Procedure:
This intermediate was prepared from 3-fluoro-4-methylphenylboronic acid and methyl 1,2,4-triazole-3-carboxylate in two steps according to the preparation of 1-(3-chloro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:37][CH2:36][C@@H:35]([F:38])[CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:49][CH:48]([CH2:50][OH:51])[CH2:47]1>>[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[O:45][CH:46]1[CH2:47][CH:48]([CH2:50][O:51][C:21]([C@@:19]23[CH2:18][N:17]([S:24]([C:27]4[CH:28]=[N:29][C:30]([N:33]5[CH2:37][CH2:36][C@@H:35]([F:38])[CH2:34]5)=[CH:31][CH:32]=4)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)=[O:22])[CH2:49]1
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2
Reactant: OCC1CC(OC2CCCCO2)C1
Product: O=C(OCC1CC(OC2CCCCO2)C1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48b using (R)-1-(4-fluorophenyl)-6-[6-((R)-3-fluoropyrrolidin-1-yl)-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and [3-(tetrahydro-pyran-2-yloxy)-cyclobutyl]-methanol. LCMS (Method G): 626.6 (M+H)+, Retention time 4.10 minutes.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH3:26]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]([CH2:24][CH2:23][O:22][CH3:21])[CH3:26])=[O:13])[CH2:8]2
Reactant: CNCCOC
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: COCCN(C)c1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and (2-methoxy-ethyl)-methyl-amine (276 mg; 3.1 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-[(2-methoxy-ethyl)-methyl-amino]-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (61 mg, 59%) as an off-white powder. ES-HRMS m/e calcd for C19H31N4O2 (M+H+) 347.2442, found 347.2438.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)([CH3:21])[CH3:22]
Reactant: CCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 57.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-ethylphenyl)amine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.68 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-ethylphenyl)urea (0.72 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:24]([O:26][CH3:27])=[O:25])[C:15](OS(C(F)(F)F)(=O)=O)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:32]([O:34][CH:35]=[CH:36][Sn](CCCC)(CCCC)CCCC)[CH3:33]>CN(C=O)C.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>[CH2:35]([O:34][CH:32]=[CH:33][C:15]1[C:14]([C:24]([O:26][CH3:27])=[O:25])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:28]=[CH:29][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:36]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC=Cc1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 79 °C
Reaction time: 9 h
Yield: 89.2 %

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-4-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (2 g, 4.62 mmol) in DMF (27 mL) was added lithium chloride (0.59 mg, 13.88 mmol). Dry nitrogen was bubbled through the mixture for for 10 min, and then dichlorobis(triphenylphosphine)palladium(II) (0.16 g, 0.23 mmol) was added. The mixture was heated to 79° C., and a solution of ethoxyvinyl tributyltin (mixture of isomers: 1,2-E:1,2-Z:1,1=1:0: 0.97:0.18) [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (1.82 g, 5.08 mmol) in DMF (23 mL). The resulting mixture was stirred for 9 h at 70° C. under nitrogen atmosphere. It was quenched with saturated sodium chloride and filtered to remove solid precipitate then concentrated. Purification by flash chromatography (Biotage) over silica gel (1:1 to 1:3, hexane/ethyl acetate) afforded the title product as brown glue (1.46 g, 89.2% yield). LCMS (APCl, M+H+): 355.2.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19]1.ClCCl>C(=O)([O-])[O-].[Na+].[Na+].CN1CCCC1=O.O>[S:18]1[CH:22]=[CH:21][C:20]([C:2]2[N:7]=[C:6]([S:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:19]1
Reactant: OB(O)c1ccsc1
Reactant: O=S(=O)(Oc1ccccc1)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=S(=O)(Oc1ccccc1)c1cccc(-c2ccsc2)n1
Temperature: 130 °C

Procedure:
A mixture of phenyl 6-bromo-2-pyridinesulfonate (D7) (1.0 g, 7.2 mmol), 3-thienylboronic acid (532 mg, 8 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II) complex with dichloromethane (80 mg) in sodium carbonate (2M solution, 5 ml) and 1-methyl-2-pyrrolidinone (8 ml) was heated at 130° C. in a microwave reactor for 5 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (1:40 to 1:5 ethyl acetate:hexanes) to afford the title product (D8). MS (ES+) m/e 318 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O>>[CH3:25][O:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:24])[CH2:5][CH2:6]1
Reactant: COCc1cccc(C=O)c1
Reactant: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)N1C1CCNCC1
Product: COCc1cccc(CN2CCC(N3C(=O)Nc4ccccc4C3c3ccc(Cl)cc3)CC2)c1

Procedure:
In similar way as in Preparation example 11, the title compound was prepared from 3-(piperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone and 3-methoxymethylbenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:22])[C:17](OCC)=[O:18])[C:11]1[CH:10]=[C:9]([C:23]#[N:24])[CH:8]=[CH:7][C:6]=1[S:5]2.[BH4-].[Na+].C(S)(S)C.[OH-].[Na+]>O1CCCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:22])[CH2:17][OH:18])[C:11]1[CH:10]=[C:9]([C:23]#[N:24])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: CCOC(=O)C(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Agent: CC(S)S
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(CO)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
A solution of ethyl (2RS)-2-(7-chloro-2-cyano-10-phenothiazinyl)propionate (157.6 g) in dry tetrahydrofuran (720 cc) is added to a suspension of sodium borohydride 25.8 g) in anhydrous tetrahydrofuran (700 cc) containing ethanedithiol (57 cc). The mixture is brought to reflux for 20 hours and then cooled to 5° C., and 4N sodium hydroxide solution (1 liter) is added slowly. The reaction mixture is diluted with methylene chloride (2 liters) and stirred for 15 minutes. The constituents of the mixture are allowed to settle and the organic phase is separated and washed with distilled water (4×1.5 liters), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column (height: 80 cm; diameter: 8 cm) of silica (0.02-0.6 mm), eluting with mixtures of ethyl acetate and cyclohexane in proportions of 15:85 (15 liters) and 36:65 (10 liters), collecting 600-cc fractions. The first 8 liters are discarded, and fractions 21 to 28 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 7-chloro-10-[(2RS)-1-hydroxy-2-propyl]-2-phenothiazinecarbonitrile (80 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[CH:15]=1
Reactant: Brc1cncc(Br)c1
Reactant: COC[C@@H]1CCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC[C@@H]1CCCN1c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of example 135 [B], (S)-2-methoxymethyl-pyrrolidine was reacted with 3,5-dibromopyridine in the presence of Pd2(dba)3, rac-BINAP and sodium tert-butoxide to give the title compound as a yellow oil. MS: 271.1, 273.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[Cl:16][C:17]1[CH:18]=[C:19]([C@H:23]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=2[F:38])=[O:28])[CH2:24][OH:25])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[NH2:1][C:2]1[C:3]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([NH:26][C@@H:23]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=3)[CH2:24][OH:25])=[O:28])=[C:30]([F:38])[CH:31]=2)=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: O=C(N[C@H](CO)c1cccc(Cl)c1)c1ccc(B(O)O)cc1F
Reactant: Nc1ncc(C2CCC(=O)NC2)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Nc1ncc(C2CCC(=O)NC2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial, 5-(6-amino-5-bromopyridin-3-yl)piperidin-2-one (45 mg, 0.167 mmol), (S)-(4-((1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)boronic acid (56.2 mg, 0.167 mmol), PdCl2(dppf) (12.19 mg, 0.017 mmol), DME (1111 μl, Ratio: 2.000), and Na2CO3 (2M solution) (555 μL, Ratio: 1.000) were added. The reaction mixture was heated at microwave reactor for 10 min at 120° C. LCMS—0.58 min, MH+483.2; 0.85 min, MH+613.3. After anhydrous sodium sulfate were added to remove water, the reaction mixture was filtered off and dried in vacuo. The small portion was purified by prep HPLC yielding 4-(2-amino-5-(6-oxopiperidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide as a diastereomeric mixture (12%). LCMS (m/z): 483.3 (MH+), 0.56 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (m, 1H), 7.80 (m, 2H), 7.42-7.30 (m, 3H), 7.30-7.24 (m, 2H), 7.25-7.15 (m, 1H), 5.18-5.03 (m, 1H), 3.87-3.64 (m, 2H), 3.47-3.35 (m, 2H), 3.11-2.97 (m, 1H), 2.46-2.30 (m, 2H), 2.08-1.91 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10].Cl[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[CH2:10][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: COc1ccc2c(Cl)nncc2c1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCCC1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Under stirring, 55% sodium hydride (3.73 g, 85.56 mmoles) was added to a solution, under nitrogen, of 3,5-dichloro-4-methyl-pyridine (13.86 g, 85.56 mmoles) in anhydrous DMF (100 ml). The mixture was kept under stirring for 1 hour then added with a solution of 1-chloro-5-cyclopentyloxy-6-methoxy-phthalazine (7.95 g, 28.52 mmoles), obtained as described in example 7, in anhydrous dimethylformamide (70 ml). After resting overnight, the mixture was quenched with water, diluted with water and extracted with ethyl acetate. The extract was washed with water and dried on sodium sulphate, then evaporated to dryness. The residue was flash chromatographed (eluent petrolatum/ethyl acetate 1:1) to give 6.58 g of the title compound (yield: 57%).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][N:15]=[C:7]3[C:6]3(OCCC[O:16]3)[C:5]=2[CH:4]=1.B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]3[CH2:12][CH2:13][CH2:14][N:15]=[C:7]3[C:6](=[O:16])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1C2=NCCCN2c2ccc(O)cc21
Temperature: -75 °C
Reaction time: 13 h
Yield: 33.5 %

Procedure:
To a cold solution of 8′-methoxy-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′pyrimido[1,2-a]indole] (0.723 g, 2.63 mmol) in anhyd. CH2Cl2 (26.4 mL) was added neat boron tribromide (0.80 mL, 8.43 mmol, 3.2 eq) drop-wise via syringe pump over a period of 55 min with cooling to −75° C. in a dry ice/iPrOH bath. The reaction was kept at about −18° C. for 13 hr then poured onto ice and neutralized to pH 7 with concentrated NH4OH keeping the reaction temperature <5° C. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was combined with the product (0.11 g) from a previous run and triturated with warm EtOAc and filtered to give the title compound as a dark red solid (0.178 g, 33% yield). NMR (300 Mz, DMSO-d6): consistent. MS: (APCI+) 203 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](/[CH:12]=[C:13](\[O:17]C)/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:19].Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](/[CH:12]=[C:13](\[OH:17])/[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:19]
Reactant: CO/C(=C\c1cc(Cl)c(N)c(C(F)(F)F)c1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Cl)cc(/C=C(\O)C(=O)O)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
10.00 kg (33.82 mol) (Z)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-methoxy-acrylic acid (C) were suspended in 20.0 L acetic acid and heated to 80° C., before 57.02 kg (338.25 mol) hydrobromic acid (48%) were added. Then the reaction mixture was stirred for 1.5 hours at 80° C., then diluted with 78.0 L water and the suspension was cooled to 22° C. The product was separated off, washed with 100.0 L water and dried.