Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([OH:16])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:43][C@@H:44]([CH2:54][CH3:55])[C@H:45]([NH:52][CH3:53])[CH2:46][N:47]1[CH2:50][CH:49]([OH:51])[CH2:48]1>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[F:20])[C:14]([N:52]([C@@H:45]([C@@H:44]([CH3:43])[CH2:54][CH3:55])[CH2:46][N:47]1[CH2:48][CH:49]([OH:51])[CH2:50]1)[CH3:53])=[O:16]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: CC[C@H](C)[C@@H](CN1CC(O)C1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
DIPEA (0.224 mL, 1.29 mmol) was added to 3,4-difluorobenzoic acid (0.068 g, 0.43 mmol) and TBTU (0.138 g, 0.43 mmol) in DCM (2 mL). The mixture was stirred at rt for 30 min. 1-((2S,3S)-3-Methyl-2-(methylamino)pentyl)azetidin-3-ol (Compound G2.1) (0.1 g, 0.43 mmol) in DCM (1 mL) was added and the resultant mixture was stirred at rt overnight. The mixture was washed with NaHCO3, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (95 mg, 68%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.61-0.74, 0.75-0.92, 0.97-1.09, 1.20-1.63, 2.33-2.45, 2.48-2.83, 3.11-3.23, 3.32-3.38, 3.39-3.53, 4.04-4.23, 5.14-5.31, 7.10-7.22, 7.28-7.41, 7.42-7.56, 7.56-7.70. Total number of protons: 24. HRMS (M+H)+: calculated 327.1884. found 327.1878. The compounds according to Examples 29.2-29.9 were prepared, from appropriate intermediates, by analogy with the method described for Example 29.1 hereinbefore.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH2:28])[CH3:27])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:18][C:19]1[CH:30]=[CH:29][C:22]2[NH:23][C:24]([C@@H:26]([NH:28][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[C:8]([CH3:16])[CH:9]=3)[CH3:27])=[N:25][C:21]=2[CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCCS1(=O)=O
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1N1CCCS1(=O)=O

Procedure:
Prepared analogously to Example 1f from 4-(1,1-dioxo-isothiazolidin-2-yl)-3-methyl-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF with subsequent extraction with ethyl acetate, drying over magnesium sulphate, activated charcoal and silica gel followed by purification on silica gel (eluant: dichloromethane/isopropanol 95:5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.BrC1C=C2C(=CC=1)C[C:35](=[O:40])CC2.N1CCCCC1>>[N:12]1([CH:7]2[CH2:6][CH2:5][C:4]3[CH:3]=[C:2]([C:35]([N:18]4[CH2:22][CH2:21][CH2:20][CH:19]4[CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:40])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: Brc1ccc2c(c1)CCC(N1CCCCC1)C2
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: C1CCNCC1
Product: O=C(c1ccc2c(c1)CCC(N1CCCCC1)C2)N1CCCC1CN1CCCC1

Procedure:
(6-Piperidin-1-yl-5,6,7,8-tetrahydro-naphthalen-2-yl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone is prepared from 1-(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidine and (S)-(+)-1-(2-pyrrolidinylmethyl)-pyrrolidine in a manner substantially analogous to Procedure A. (See herein Example 1). Starting material, (6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidine, was prepared from 6-bromo-2-tetralone and piperidine in a manner substantially analogous to Preparation 1. Mass Spectrum (ES+) 396.
Reaction SMILES: [CH2:1]([CH:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])[CH3:2].[CH2:11](Br)[CH:12]=[CH2:13].C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH2:1]([C:3]([CH:8]([CH3:10])[CH3:9])([CH2:13][CH:12]=[CH2:11])[C:4]([O:6][CH3:7])=[O:5])[CH3:2]
Reactant: CCC(C(=O)OC)C(C)C
Reactant: C=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC(CC)(C(=O)OC)C(C)C
Yield: 81.7 %

Procedure:
The reaction of methyl 2-ethyl-3-methylbutyrate (23.76 g, 165 mmol), prepared as in Lion C, Dubois J E (1981) supra., with allyl bromide (31.34 g, 259 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (25.05 g, 248 mmol) with butyllithium in hexanes (2.5M, 94.4 mL, 236 mmol)) in THF (330 mL) and HMPA (24.7 mL, 142 mmol), as described above in the preparation of Example 7, followed by the vacuum distillation of crude product afforded the pure olefinic ester (24.85 g, 82%) as a colorless liquid: bp 92°-94° C. (20 mmHg).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[N:41][CH:42]=1>>[CH:46]1([NH:45][C:43]([C:40]2[N:39]=[CH:38][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)=[O:44])[CH2:48][CH2:47]1
Reactant: O=C(NC1CC1)c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(C(=O)NC3CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one and 5-bromo-N-cyclopropylpyrimidine-2-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.167 min, m/z=515.2; 1H NMR (CDCl3) 0.65 (m, 2H), 0.87 (m, 2H), 1.09 (m, 6H), 1.51 (m, 3H), 2.26 (m, 2H), 2.31 (m, 2H), 2.43 (m, 3H), 2.83 (m, 1H), 2.98 (m, 1H), 5.67 (m, 1H), 7.06 (m, 1H), 7.25 (m, 7H), 8.02 (m, 1H), 8.89 (m, 2H)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.C(O)C[OH:32]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][OH:32])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: OCCO
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: CN(Cc1cccs1)C1=C(C(=O)OCCO)C(=O)C(=Cc2c[nH]c3ncccc23)O1
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, ethylene glycol (0.20 mL, 3.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.0061 g, y. 10%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH2:28]([O:30][CH:31]([C:45]([O:47]CC)=O)[NH:32][C:33](=[O:44])[C:34]1[C:35](=[C:39]([F:43])[CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=O)[CH3:29].C(OC(C(OCC)=O)NC(=O)C1C(=CC=CC=1F)C(O)=O)C.[CH2:72]([O:79][C:80](=[O:92])/[N:81]=[C:82](\[NH2:91])/[C:83]1[CH:88]=[CH:87][C:86]([CH2:89][NH2:90])=[CH:85][CH:84]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>>[CH2:72]([O:79][C:80](=[O:92])/[N:81]=[C:82](\[NH2:91])/[C:83]1[CH:84]=[CH:85][C:86]([CH2:89][NH:90][C:45](=[O:47])[CH:31]([O:30][CH2:28][CH3:29])[N:32]2[C:36](=[O:38])[C:35]3[C:34](=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[C:33]2=[O:44])=[CH:87][CH:88]=1)[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1
Reactant: CCOC(=O)C(NC(=O)c1cccc(F)c1C(=O)O)OCC
Agent: CCOC(=O)C(NC(=O)c1c(F)cccc1C(=O)O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCOC(C(=O)NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1)N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure C, but using 2.2 eq. of BOP coupling reagent and adding the amine component after a delay time of 1 h, (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-6-fluoro-phthalamic acid and its regioisomer (RS)-N-(ethoxy-ethoxycarbonyl-methyl)-3-fluoro-phthalamic acid was reacted with [1-amino-1-(4-aminomethyl-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester to give (RS)-[1-amino-1-(4-{[2-ethoxy-2-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-methyl}-phenyl)-meth-(Z)-ylidene]-carbamic acid benzyl ester, MS 533.4 ([M+H]+).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:42])[NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H].C(Cl)(Cl)Cl>CO.C1COCC1.[Pd]>[O:39]1[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][NH:33][C:32]([C:29]2[CH:30]=[CH:31][C:26]([N:23]3[CH2:22][CH2:21][CH:20]([NH:19][C:17]([N:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)=[O:18])[CH2:25][CH2:24]3)=[CH:27][CH:28]=2)=[O:42])[CH2:37][CH2:38]1
Reactant: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCNCC3)CC2)cc1

Procedure:
The 4-benzyloxycarbonyl-N-(1-(4-(2-morpholinoethylcarbamoyl)-phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (14.5 g, 25.0 mmol) obtained in Example 15(4) was dissolved in methanol (80 ml) and THF (80 ml), and 10% Pd—C (3.0 g) was added thereto, followed by stirring at room temperature in a hydrogen atmosphere for 17 hours. To the reaction mixture, chloroform was added. After the insoluble material was filtered with Celite, the filtrate was evaporated under reduced pressure, thereby obtaining N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (11.2 g, quant.) as a milky-white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1CSCCN1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCSCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (2.87 g, 25 mmol) in 15 mL of methylene chloride was added thiomorpholine (2.50 g, 24 mmol) and triethylamine (4.9 g, 48 mmol) slowly. The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (200 mL) was added. The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and the filtrate was concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 1.83 g (42.0%) of 4-(2-chloroacetyl) thiomorpholine as a brown liquid. 1HNMR (300 MHz / CDCl3):δ 2.62 (t, 2H, J=5.03 Hz), 2.68 (t, 2H, J=4.93Hz), 3.75 (t, 2H, J=5.04 Hz), 3.85 (t, 2H, J=5.04 Hz), 4.04 (s, 2H); mass spectrum, m/z =180.2 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([O:13][NH:14]C(=O)OC(C)(C)C)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.O>ClCCl>[C:6]([O:10][C:11]([O:13][NH:14][C:1](=[O:4])[CH:2]=[CH2:3])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)NOC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of tert-butyl N-(tert-butoxycarbonyloxy)carbamate (31) and N,N-diisopropylethylamine in dry dichloromethane was added. Water was added after 16 hours of reaction and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (90:10). The purification gave N-(tert-butoxycarbonyl), N-(tert-butoxycarbonyloxy)acrylamide (32).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.Cl[CH2:20][O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][O:21][CH2:20][N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: CC(C)(C)COCCl
Product: Cc1c(-c2cccnc2)n(COCC(C)(C)C)c2ccc(C#N)cc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) and 1-chloromethoxy-2,2-dimethyl-propane are processed according to the method described in Example 68 to give 1-(2,2-dimethyl-propoxymethyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, MeOD) δ ppm 0.84 (s, 9H), 2.33 (s, 3H), 3.04 (s, 2H), 5.48 (s, 2H), 7.59 (dd, J=8.6, 1.5 Hz, 1H), 7.66 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.77 (dd, J=8.6, 0.5 Hz, 1H), 8.07 (dt, J=7.8, 1.9 Hz, 1H), 8.09 (dd, J=1.5, 0.8 Hz, 1H), 8.70 (dd, J=4.9, 1.6 Hz, 1H), 8.75 (dd, J=2.3, 0.8 Hz, 1H). HRMS (ESI) m/z 334.1914 [(M+H)+ Calcd for C21H24N3O: 334.1919].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:28]=[C:29]1[NH:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=3)[C:15](=[O:26])[N:14]2[CH3:27])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([N:30]3[CH2:31][CH2:32][CH2:33][NH:34][C:29]3=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: COC(=O)c1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 176 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxycarbonyl-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.28 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.126 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.370 g); mp 185°-190° C. (d); MS: m/z=573(M+1); NMR(CD3 SOCD3): 1.02 (s,1), 1.14 (m,1), 1.69-1.93 (m,5), 3, 14 (s,3), 3.94 (s,3), 4.59 (m,1), 4.79, 4.79 (s,1), 6.6 (d,1, J=8), 6.89 (s,1), 7.16 (d,1, J=81), 7.86 (d,1, J=8), 8.33 (m,2). Analysis for C29H34 Cl2N4O4.1.5 H2O.1.0 HCl: Calculated: C, 54.68; H, 6.01, N, 8.80; Found: C, 54.86; H, 5.98; N, 8.89.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2([O:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[CH2:23][CH2:22]2)=[CH2:20])=[CH:15][CH:14]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:21]3([O:24][C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[CH2:22][CH2:23]3)[CH2:20][O:9]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(c1ccc(Cl)cc1)C1(Oc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccc(OC2(C3(c4ccc(Cl)cc4)CO3)CC2)cc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 4.3 g=25 mmol of 80% strength m-chloroperbenzoic acid in 100 ml of chloroform was added dropwise at 20° C. with stirring to a solution of 6.1 g=20 mmol of 1-(4-chlorophenyl)-1-[1-(4-chlorophenoxy)-cyclopropan-1-yl]-ethene (compound from Example 12) in 20 ml of chloroform, and the mixture was stirred for 15 hours at 20° C. and 3 hours under reflux. For work-up, the mixture was shaken three times with 50 ml of 2N sodium hydroxide solution and once with 2N sodium bisulfite solution, washed with water and dried over sodium sulfate, and the solution was concentrated in a water-pump vacuum. The residue was dissolved in twice the volume of ether. After seeding using a crystal from Example 2a, 3.2 g of melting point 96°-97° C. crystallized.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1)[CH2:4][OH:5].[CH3:19][P:20](Cl)(Cl)=[O:21]>C(Cl)Cl.O>[CH3:19][P:20]1(=[O:21])[O:5][CH2:4][CH:3]([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:8][CH:7]=2)[CH2:2][O:1]1
Reactant: CC(C)(C)OC(=O)c1ccc(C(CO)CO)cc1
Reactant: CP(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C2COP(C)(=O)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-[2-hydroxy-1-(hydroxymethyl)ethyl]benzoate (440 mg, 1.74 mmol) and TEA (510 μl, 3.66 mmol) were taken up in CH2Cl2 (20 mL) and cooled to 0° C. Methylphosphonic dichloride (193 μl, 2.09 mmol) in CH2Cl2 (10 mL) was added dropwise over 30 minutes. The reaction was then allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) allowed separation of residual starting material from the diastereomeric products, but the diastereomers coeluted. Flash chromatography of the mixed diastereomers with 25-100% EtOAc/hexanes slowly eluted the first diastereomer, and the same column was flushed with 2-10% MeOH/CH2Cl2 to push off the second diastereomer (both were obtained as colorless solids). 1H NMR (CDCl3, 600 MHz) Diastereomer 1: δ 7.95 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 4.70-4.65 (m, 2H), 4.24-4.17 (m, 2H), 3.54-3.47 (m, 1H), 1.63 (d, J=18.0 Hz, 3H), 1.56 (s, 9H). Diastereomer 2: δ 7.97 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 4.66-4.59 (m, 2H), 4.36-4.30 (m, 2H), 3.50-3.45 (m, 1H), 1.62 (d, J=17-3 Hz, 3H), 1.57 (s, 9H). MS: cal'd 313 (MH+), exp 313 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[K+].[K+].Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:5]=1[N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1cc(C)cc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc(Br)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 48 h
Yield: 82 %

Procedure:
To a sired solution of 2.0 g (4.8 nmnol) of the product of Example 135 in 20 mL of DMF was added 1.0 g (10 mmol) of K2CO3 and 1.1 g (7.2 mmol) of 3-picolyl chloride hydrochloride. The reaction niixture was stirred for 48 h at room tempera and then diluted with water. The resulting mixture was extracted with chloroform and the combined organic layers were washed with water, dried over MgSO4, filtered and concentraed in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate. hexane (1:1) to provide 2.90 g (82%) of the desired product as a brown oil. Electrospray Mass Spec: 508 (M+H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1.[NH2:34][CH2:35][CH:36]([C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[OH:37]>>[OH:37][CH:36]([C:38]1[CH:39]=[CH:40][C:41]([N+:44]([O-:46])=[O:45])=[CH:42][CH:43]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: NCC(O)c1ccc([N+](=O)[O-])cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc([N+](=O)[O-])cc2)N(C(=O)c2ccc(-c3ccccn3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(2-pyridinyl)benzoic acid, and (1RS)-2-amino-1-(4-nitrophenyl)ethanol, the title compound was obtained in 63% purity by HPLC. MS(ESI+): m/z=504.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1>CO.CC(C)=O.CC(O)=O>[CH3:1][N:2]([CH3:3])[CH2:25][C:23]1[N:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][C:16]=2[N+:27]([O-:29])=[O:28])[S:21][CH:22]=1
Reactant: Cc1ccc(-c2nc(C=O)cs2)c([N+](=O)[O-])c1
Reactant: CNC
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2nc(CN(C)C)cs2)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Dimethylamine (640 uL of a 2M solution in MeOH), sodium acetate, and sodium cyanoborohydride (56 mgs, 0.89 mmol) were stirred in 2.6 mL MeOH at room temperature under N2. Glacial HOAc was added to adjust the pH to 7-8. 2-(4-Methyl-2-nitro-phenyl)thiazole-4-carbaldehyde (159 mgs, 0.64 mmol) then was added as a solution in 3.2 mL of MeOH. After 2 h, product formation was apparent by mass spectroscopy. The reaction was allowed to proceed overnight. At that time, acetone (500 uL) was added to quench any unreacted borohydride and the reaction acidified to pH<3. The reaction was concentrated. The residue was partitioned between Et2O (30 mL) and H2O (30 mL). The aqueous phase was extracted with Et2O, then neutralized with 1N NaOH to pH 10. The aqueous phase was re-extracted with Et2O. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to provide the desired material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)=[C:4]([F:19])[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([NH:38][C:14]([C:13]4[CH:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:19])[NH:9][C:10](=[O:18])[NH:11][C:12]=4[CH3:17])=[O:16])[CH:36]=3)[NH:31][N:30]=2)[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1ccc2[nH]nc(Nc3cc(F)cc(F)c3)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)NC(=O)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4cc(F)cc(F)c4)c3c2)C(c2ccc(Cl)cc2F)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(4-Chloro-2-fluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(3,5-difluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=527 [M+H]+.