Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]([OH:23])[C:20]([OH:22])=O)=[O:16])[N:9]=2)=[CH:4][CH:3]=1.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][NH2:43]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:19]([OH:23])[C:20](=[O:22])[NH:43][CH2:42][CH2:41][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1
Reactant: NCCc1ccccn1
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NCCc1ccccn1)c1cccnc1-n1ccc(-c2ccc(F)cc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-(4-fluorophenyl)-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with 2-(pyridin-2-yl)ethylamine; ESI-MS [M+H]+: 565.2
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[C:4]([N+:28]([O-])=O)[CH:3]=1.O.[Cl-].[NH4+]>O1CCCC1.C(O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([O:24][CH3:25])[CH:9]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2OC)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(COc2ccc(CNc3ccc(Br)cc3N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
To a stirred suspension of 4-bromo-N-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-2-nitroaniline (7.71 g, 16.30 mmol) in tetrahydrofuran (100 mL), ethanol (25 mL), and water (25 mL) was added ammonium chloride (0.44 g, 8.15 mmol) and iron powder (9.10 g, 163 mmol). The mixture was heated to reflux. After 5 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite with the aid of ethanol. The filtrate was concentrated, and the residue partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate, filtered, and concentrated to provide 6.73 g (95%) of 4-bromo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine as a brown solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:13]1([C@@H:19]([NH:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1
Temperature: 3 °C
Yield: 111.6 %

Procedure:
Ethyl 2-oxocyclohexane carboxylate (6, 484.9 g) and (S)-(−)-1-phenylethylamine (7, 362.5 g) were charged into an RB flask followed by heptanes (1.5 L) and Ytterbium (III) trifluoromethane sulfonate (8.8 g). The contents were heated to reflux for 3 hours and the liberated water was removed simultaneously and then cooled to 22° C. (±3° C.). The insoluble material was filtered and the filtrate was concentrate on a rotary evaporator under vacuum to afford 869.4 g of (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH3:26][S:27][CH2:28][CH2:29][NH2:30].O>C(#N)C>[CH3:26][S:27][CH2:28][CH2:29][NH:30][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CSCCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSCCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 97.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in acetonitrile (5 mL) was added potassium carbonate (321 mg, 1.55 mmol) and 2-(methylthio)ethylamine (127 mg, 1.39 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (373 mg, 98% yield) as red crystals.
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[C:19]([Si:22]([CH3:24])([CH3:23])[O:12][CH2:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC/C=C/Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC/C=C/Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation example 236, 6.3 g, 38.83 mmol) in CH2Cl2 was added imidazole (3.4 g, 50.48 mmol) and TBDMS-Cl (7.6 g, 50.48 mmol) at 0° C. then stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (10.6 g, 80˜98%)
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:41])[C:22]=1[N:23]1[CH2:29][C:28]([O:31][CH3:32])([CH3:30])[CH2:27][CH:26]([NH:33]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47]([F:62])[C:48]=1[Sn](CCCC)(CCCC)CCCC>>[NH2:8][C:9]1[S:13][C:12]([C:48]2[C:47]([F:62])=[CH:46][N:45]=[CH:44][C:43]=2[F:42])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:41])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:33])[CH2:27][C:28]([O:31][CH3:32])([CH3:30])[CH2:29]1)=[O:16]
Reactant: COC1(C)CC(NC(=O)OC(C)(C)C)CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Product: COC1(C)CC(N)CCN(c2c(NC(=O)c3nc(-c4c(F)cncc4F)sc3N)cnn2C)C1

Procedure:
Following the procedure for Example 422 starting from tert-butyl 1-(4-(5-(tert-butoxy-carbonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-methoxy-6-methylazepan-4-ylcarbamate and 3,5-difluoro-4-(tributylstannyl)pyridine gave 440 as the monoformate salt as a white solid (67 mg, 43% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.84 (s, 1H), 8.70 (s, 2H), 8.45 (s, 1H), 7.82 (s, 2H), 7.70 (s, 1H), 3.68 (s, 3H), 3.52 (t, J=11.2 Hz, 2H), 3.36-3.19 (m, 3H), 3.13-3.04 (m, 1H), 3.04 (s, 3H), 2.98 (d, J=14.4 Hz, 1H), 2.18 (d, J=14.2 Hz, 1H), 2.12-1.98 (m, 1H), 1.85-1.75 (m, 1H), 1.68-1.57 (m, 1H), 1.03 (s, 3H). LCMS (ES+) m/z 493 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:44]([C:46]1[CH:47]=[C:48](B(O)O)[CH:49]=[CH:50][CH:51]=1)=[O:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:15]3[CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[CH:48][CH:47]=[C:46]([CH:44]=[O:45])[CH:51]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[CH:14]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(Br)c2)c1
Reactant: O=Cc1cccc(B(O)O)c1
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: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Yield: 67.1 %

Procedure:
N-[(3-Bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (0.849 g, 1.303 mmol), (3-formylphenyl)boronic acid (0.195 g, 1.303 mmol), potassium carbonate (0.540 g, 3.91 mmol), and Pd(Ph3P)4 (0.075 g, 0.065 mmol) were divided into 3 portions and added to three 2-5 mL Biotage microwave vials in 1,4-dioxane (3 mL) and water (1 mL). The vials were capped and the mixtures were microwaved at normal power in the Emrys Optimizer at 100° C. for 15 min. The combined crude product was partitioned between EtOAc (75 mL) and water (20 mL). The phases were separated, and the organic phase was washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na2SO4 filtered and evaporated to give the crude material. It was taken up in DCM and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give (N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (596.6 mg, 0.874 mmol, 67.0% yield)) as a beige solid. LC-MS m/z 677.4 (M+H)+, 1.01 min (ret time); mp 107-110° C.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:44])([CH3:43])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73](O)=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:64]([C:76]([O:78][CH2:79][CH:80]1[C:92]2[C:87](=[CH:88][CH:89]=[CH:90][CH:91]=2)[C:86]2[C:81]1=[CH:82][CH:83]=[CH:84][CH:85]=2)=[O:77])[C@H:65]([C:73]([NH:1][C@H:2]([C:15]([N:17]1[CH2:63][CH2:62][CH2:61][C@H:18]1[C:19]([N:21]1[CH2:60][CH2:59][CH2:58][C@H:22]1[C:23]([NH:25][C@H:26]([C:52]([C:54]([CH3:55])([CH3:57])[CH3:56])=[O:53])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:51])[NH:32][S:33]([C:36]1[C:49]([CH3:50])=[C:47]([CH3:48])[C:46]2[O:45][C:42]([CH3:43])([CH3:44])[CH2:41][CH2:40][C:39]=2[C:37]=1[CH3:38])(=[O:35])=[O:34])=[O:24])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[O:74])[C@@H:66]([CH3:72])[O:67][C:68]([CH3:70])([CH3:71])[CH3:69]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)[C@@H](C)OC(C)(C)C)C(=O)C(C)(C)C)c(C)c2c1OC(C)(C)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
H-Lys(Boc)-Pro-Pro-Arg(Pmc)-t-Bu (3.55 g, 3.86 m mmol) was added to a solution of the activated acid prepared from Fmoc-Thr(t-Bu)-OH (1.6 g, 4 mmol) and HATU (1.9 g, 5 mmol) and DIEA (1.29 g, 10 mmol) in dry CH2Cl2 (25 ml) and stirred for 20 h at RT.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[C:16](O)[N:15]=[CH:14]3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)(O)[O-].[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:16]1[N:15]=[CH:14][C:13]2[C:18](=[CH:19][C:20]([F:21])=[C:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH:12]=2)[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)cc(-c2cc3cnc(O)nc3cc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)cc(-c2cc3cnc(Cl)nc3cc2F)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 6-(3,5-dimethoxyphenyl)-7-fluoroquinazolin-2-ol (2.0 g, 6.7 mmol) in POCl3 (30 mL) was heated at 135° C. for 2 hours. After that, the reaction solution was cooled to room temperature and dropwise added to saturated sodium bicarbonate solution (800 mL) at 0° C. The mixture was extracted with ethyl acetate (200 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (1.1 g, 52%) as a pale yellow solid. MS (ES+) C16H12ClFN2O2 requires: 318, found: 319 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[SH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+].O>CO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][S:13][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1)[CH3:19]
Reactant: CCOC(=O)CS
Reactant: Clc1nc(-c2ccccc2)no1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CSc1nc(-c2ccccc2)no1
Reaction time: 3 h
Yield: 75 %

Procedure:
5-chloro-3-phenyl-1,2,4-oxadiazole (36 parts) was added portionwise to a solution of ethyl mercaptoacetate (24 parts) and sodium methoxide (11 parts) in methanol (500 parts). The temperature rose to about 50° C. and the mixture was allowed to stand for three hours. The product was poured into an excess of cold water, and extracted with benzene, washed with water and the solvent then evaporated off. Recrystallisation gave ethyl(3-phenyl-1,2,4-oxadiazol-5-ylthio)acetate (40 parts, 75% yield), melting point 50-52° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)([N:36]1C=CN=C1)=O.[NH4+].[OH-].O>C1COCC1>[C:20]([CH2:19][C@@H:18]([N:5]1[C:6](=[O:17])[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=2[NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])[CH2:4]1)[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)(=[O:21])[NH2:36]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(N)=O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (0.62 g, 1.3 mmol) in THF (5 ml) was added carbonyldiimidazole (0.3 g, 2 mmol) at room temperature. The solution was stirred for 2 hrs at room temperature. To the mixture was added NH4OH (13.8 N, 0.3 ml, 3.9 mmol). The resulting mixture was stirred at room temperature for 4 hrs. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and to the resulting mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was stirred with ether (5 ml) for 2 hrs and filtered to give (1R)-cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(3-ethoxy-4-methoxy-phenyl)-ethyl]-7-chloro-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.5 g, 82%): mp 201-203° C.; 1HNMR (CDCl3): δ 0.88-0.91 (m, 2H, c-CH2), 1.08-1.11(m, 2H, c-CH2), 1.45 (t, J=7.5 Hz, 3H, OCH2CH3), 1.65-1.68 (m, 1H, c-CH), 2.98 (dd, J=5, 16 Hz, 1H, CHH), 3.36 (dd, J=5, 16 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.13 (d, J=17 Hz, 1H, NCHH), 4.35 (d, J=17 Hz, 1H, NCHH), 5.42 (broad s, 1H), 5.58-5.64 (m, 1H, CHN), 6.00 (broad s, 1H), 6.83-6.95 (m, 3H, Ar), 7.36 (d, J=9 Hz, 1H, Ar), 8.43 (d, J=9 Hz, 1H, Ar), 10.41 (s, 1H); 13C NMR (CDCl3): 8.4, 14.7, 16.1, 38.6, 48.6, 46.7, 53.2, 53.4, 56.0, 64.5, 65.8, 112.2, 119.0, 119.1, 119.5, 121.8, 130.6, 132.8, 136.6, 139.1, 148.7, 149.4, 169.0, 171.8, 172.6; Anal. Calcd. for C24H26ClN3O5: C, 61.08; H, 5.55; N, 8.90; Found: C, 60.89; H, 5.42; N, 8.51.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[N:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl.C(NCC)C>ClCCl>[CH:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@H:6]1[O:8][C:19](=[O:21])[N:12]([CH2:13][CH3:14])[CH2:17][CH3:16])([CH3:11])[CH3:10]
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 0 °C
Yield: 48.9 %

Procedure:
30 mmol of l-menthol were placed with 110 ml dichlormethane in a 250 ml vessel at room temperature and 3.08 g (39 mmol) of pyridine were added. The reaction mixture was cooled to 0° C. and 3.56 g (12 mmol) of triphosgene in 15 ml dichlormethane were added dropwise. After five minutes 2.37 g (30 mmol) pyridine were added. Subsequently, 2.19 g (30 mmol) of diethylamine in 15 ml dichlormethane were added dropwise, the resulting mixture was allowed to come to ambient temperature and then quenched with water. After separation of the phases, the water phase was extracted once with dichlormethane and the combined organic phases were concentrated. The raw product was purified by distillation and column chromatography to yield 1.5 g of the desired product as a mixture of isomers with a purity of 99.4%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[CH3:16])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[C:6]=1[CH3:16])[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1C
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1C

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Methyl-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C(OC[N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:16]=[C:17]([CH:44]=[CH:45][CH:46]=2)[C:18]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([N:28]2[CH2:33][CH2:32][C@@:31]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)([OH:34])[C:30]([CH3:43])([CH3:42])[CH2:29]2)=[O:27])=[O:19])=[N:11]1)C1C=CC=CC=1.C(O)C1C=CC=CC=1>CO>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C@@:31]2([OH:34])[CH2:32][CH2:33][N:28]([C:26]([C@H:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[NH:20][C:18](=[O:19])[C:17]3[CH:44]=[CH:45][CH:46]=[C:15]([C:12]4[N:11]=[N:10][NH:14][N:13]=4)[CH:16]=3)=[O:27])[CH2:29][C:30]2([CH3:42])[CH3:43])=[CH:40][CH:39]=1
Reactant: CC1(C)CN(C(=O)[C@H]2CCC[C@H]2NC(=O)c2cccc(-c3nnn(COCc4ccccc4)n3)c2)CC[C@]1(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: OCc1ccccc1
Product: CC1(C)CN(C(=O)[C@H]2CCC[C@H]2NC(=O)c2cccc(-c3nn[nH]n3)c2)CC[C@]1(O)c1ccc(Cl)cc1

Procedure:
Example 24 was prepared from 3-(2-(benzyloxymethyl)-2H-tetrazol-5-yl)-N-((1R,2S)-2-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)cyclopentyl)benzamide using similar conditions as described in Example 22. MS (ESI+)=523 (M)+. 1H NMR (CD3OD, 500 MHz) (NMR shows several rotamers) (NMR indicates contamination with 0.5 eq. (mol) of benzyl alcohol—chemical shifts for contaminant not reported) δ 8.46 (s, 0.3H), 8.39 (s, 0.7H), 8.24 (d, J=8.0 Hz, 0.3H), 8.20 (d, J=8.0 Hz, 0.7H), 7.97 (d, J=8.3 Hz, 0.3H), 7.91 (d, J=8.3 Hz, 0.7H), 7.73 (t, J=7.8 Hz, 0.3H), 7.67 (t, J=7.7 Hz, 0.7H), 7.45 d, J=8.8 Hz, 1.4H), 7.33 d, J=8.8 Hz, 0.6H), 7.28 (d, J=8.5 Hz, 1.4H), 7.19 (d, J=8.5 Hz, 0.6H), 4.79 (q, J=7.4 Hz, 0.7H), 4.62-4.54 (m, 0.6H), 4.15-4.06 (m, 0.7H), 4.02 (d, J=12.7 Hz, 0.7H), 3.66-3.51 (m, 2.3H), 3.18-3.06 (m, 0.3H), 2.94 (d, J=12.4 Hz, 0.7H), 2.71 (td, J=13.5, 4.7 Hz, 0.7H), 2.49 (td, J=13.3, 4.4 Hz, 0.3H), 2.29-1.80 (m, 5H), 1.76-1.63 (m, 1H), 1.53 (d, J=14.0 Hz, 0.7H), 1.50-1.44 (m, 0.3H), 0.80 (s, 0.8H), 0.77-0.68 (m, 5.2H). [LCMS method: Inj. Vol.=10 uL; Start % B=0; Final % B=100; Gradient Time=2 min; Flow Rate=5 ml/min; Wavelength=220 nm; Solvent A=10% MeOH-90% H2O-0.1% TFA; Solvent B=90% MeOH-10% H2O-0.1% TFA; Column 1=Sunfire S5 C18 4.6×30 mm (2 min grad); Retention Time=1.90 minutes.]
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29]N>C(O)C>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[CH2:26][S:27][CH2:28][CH2:29][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: NCCSCc1nccs1
Reactant: COc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: CCO
Product: COc1ccc(Cc2cnc(NCCSCc3nccs3)[nH]c2=O)cn1
Yield: 60 %

Procedure:
An equimolar mixture of 2-nitroamino-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone and 2-(2-thiazolylmethylthio) ethylamine was refluxed in ethanol for 18 hours. The solid which crystallised out on cooling was recrystallised from ethanol to give 2-[2-(2-thiazolylmethylthio)ethylamino]-5-(6-methoxy-3-pyridylmethyl)-4-pyrimidone, m.p. 95-97° in 60% yield.