Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[O:15][CH2:16][O:17][C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:26]=[O:27])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.ClCCl.CCCCCC>ClC1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:26]=[O:27])=[C:11]2[O:15][CH2:16][O:17][C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc(COc2cccc3c2OCO3)cc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=Cc1ccc(OCc2ccccc2)c2c1OCO2
Temperature: -5 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
1-Benzyloxy-2,3-methylenedioxybenzene (47.8 g) in chlorobenzene (50 ml) was added dropwise to a mixture of N-methylformanilide (34 g) and phosphorus oxychloride (38.5 g) in chlorobenzene (50 ml) maintained at -5° C. When the addition was complete the reaction mixture was allowed to warm to room temperature. It was then poured onto ice, and stirred overnight. The resulting mixture was extracted with ethyl acetate, washed with water and brine, and then dried and evaporated to yield 47.9 g of crude product as an isomeric mixture of aldehydes. Silica gel chromatography using 1:1 dichloromethane-hexane afforded 7 g of 4-benzyloxy-2,3-methylenedioxybenzaldehyde, mp 81°-82° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:18])[CH3:2].F[B-](F)(F)F.[CH3:31][O+](C)C>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[C:8]([CH3:18])=[CH:9][C:10]2[C:14]([CH:15]=1)=[N:13][N:12]([CH3:31])[C:11]=2[CH2:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc2[nH]nc(CC)c2cc1C
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: CCOC(=O)CN(CC(=O)OCC)c1cc2nn(C)c(CC)c2cc1C
Yield: 33 %

Procedure:
Using the compound (722 mg, 2.08 mmol) of step C, and trimethyloxonium tetrafluoroborate (527 mg, 3.56 mmol), and according to the method of Reference Example 137, step F, the title compound (248 mg, yield 33%) was obtained as a yellow oil.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:5](=O)[N:4]2[CH2:16][CH2:17][CH2:18][C:3]12[C:19](OCC)=[O:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[C:9]1([CH2:8][N:7]2[CH2:6][CH2:5][N:4]3[CH2:16][CH2:17][CH2:18][C:3]3([CH2:19][OH:20])[CH2:2]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C12CCCN1C(=O)CN(Cc1ccccc1)C2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC12CCCN1CCN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
To a solution of ethyl 1,4-dioxo-2-(phenylmethyl)hexahydropyrrolo[1,2-a]pyrazine-8a(6H)-carboxylate (D65, 450 mg) in anhydrous THF (5 mL) under a Nitrogen atmosphere at 0° C., lithium aluminium hydride (1M in THF, 14 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 10 minutes, then allowed to reach rt and stirred at this temperature for 45 minutes. It was then heated at reflux temperature for 3.5 hours and then allowed to cool to r.t. Water (540 microL), NaOH (1M solution, 540 microL) and water (1.6 mL) were then added to the solution and the formation of a white precipitate was observed. The suspension was stirred at rt for 30-40 minutes then filtered over a Gooch funnel. The organic filtrate was dried and concentrated in vacuo to a residue which was purified by flash chromatography (DCM/MeOH from 100/0 to 90:10) to give the desired compound (162 mg) as orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[N:40]1([C:48](=O)[CH2:49]Cl)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:48][CH2:49][O:39][C:38]2[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]3[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=3[CH:16]3[CH2:25][CH2:24][C:23]4[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=4[CH2:17]3)=[CH:3][C:2]=2[F:1])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCCCC3)c(F)c2)C(C)C)c1
Yield: 35.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-azocan-1-yl-2-chloroethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NCCCCO
Yield: 98.3 %

Procedure:
2-Fluoronitrobenzene (28 g), 4-aminobutanol (18 g) and triethylamine (29 ml) were dissolved in toluene (100 ml) and heated at 100° for 6 hours. The organic phase was washed with water (50 ml) and then extracted with concentrated hydrochloric acid (2×50 ml). The combined acid extracts were diluted with water (100 ml), neutralised with concentrated aqueous ammonia and extracted with methylene chloride (3×50 ml). The organic extracts were combined, dried over Na2SO4, filtered and evaporated to leave the title compound as a dark red oil (41 g) which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: c1ccncc1
Product: Cc1ccc(C#N)c(NS(=O)(=O)c2ccc(F)cc2)c1
Temperature: 0 °C
Yield: 43.7 %

Procedure:
The title compound was synthesized by reacting 2-amino-4-methylbenzonitrile (0.25 g, 1.89 mmol) and 4-fluoro-benzenesulphonyl chloride (0.37 g, 1.89 mmol) in 2 mL of dry pyridine, following the reaction procedure of 6.29 The concentrated reaction mixture was poured into ice cold water (300 mL), and resulting pale white solid was filtered, washed with water and dried to gave 13 (0.24 g, 42.8%). Crystallization with EtOH gave (0.15 g) white amorphous solid, mp: 130-132° C.; IR (CHCl3) 3260, 2226, 1376, 1340, 1171, 1156 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.42 (s, 3H, CH3) and 6.90-7.83 (m, 7H, aromatic). HRMS calcd 313.0417 (C14H11FN2O2S.Na+), found 313.0418.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][CH2:33][C@H:34]1[N:38]([CH3:39])[C:37](=[O:40])[CH2:36][CH2:35]1.O[C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1>O1CCCC1>[CH3:39][N:38]1[C@H:34]([CH2:33][O:32][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[CH2:35][CH2:36][C:37]1=[O:40]
Reactant: CN1C(=O)CC[C@H]1CO
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1COc1cccnc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1.57 g (6.0 mmole) triphenylphosphine in 30 ml dry tetrahydrofuran under argon atmosphere at −15° C. 0.95 ml (1.05 g, 6.0 mmole) diethyl azodicarboxylate was added, drop by drop for 5 minutes, then 0.517 g (4.0 mmole) (S)-5-(hydroxymethyl)-1-methylpyrrolidin-2-one in 5 ml dry tetrahydrofuran and 0.40 g (4.2 mmole) 3-hydroxypyridine were added and stirred for 10 minutes, then kept overnight in a refrigerator at −20° C. The solution was evaporated at 35° C. in good vacuum; the residue was dissolved in 15 ml of dichloromethane and washed with 1×7 and 2×2 ml of 1M hydrochloric acid. To the combined acidic solutions 20 ml saturated aqueous sodium bicarbonate solution was carefully added and then further 1 g of solid sodium bicarbonate was added, and this was extracted with 5×10 ml dichloromethane. The combined organic solutions were dried over magnesium sulfate, evaporated on a rotavapor at 35° C. and the residue was purified by column chromatography on 30 g silica gel, and developing with benzene containing 30% of diethylamine; this furnished 0.252 g (31%) of pure product.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)C>[Pd].ClCCl>[F:21][C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: OC1(c2cccc(F)c2F)CCNC1
Yield: 118.9 %

Procedure:
Preparation according to preparation 4: (−)-1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (5.5 g, 19 mmol), ammonium formiate (3 g, 48 mmol), ethanol (100 mL) and palladium on carbon (300 mg). Refluxed for 35 min. Dichloromethane/tert-butylmethyleter (1:1, 100 mL) was added and the mixture was filtrated through celite, the filtrate was evaporated to give the title compound (4.5 g). MS m/z (relative intensity, 70 eV) 199 (M+100) 141 (82), 113 (61), 124 (59), 63 (45).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:17])[C:4]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19].C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C1COCC1.C(=O)([O-])O.[Na+]>[C:34]([O:37][CH2:38][C:39]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18]([C:4]2[N:5]([CH3:17])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8](=[O:16])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:19])[CH2:22][CH2:23]1)=[O:40])(=[O:36])[CH3:35]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)[nH]c1ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)[nH]c1ccccc12
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 3-methoxy-1-methyl-4-oxo-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide (300 mg, 0.87 mmol) and triethylamine (88 mg, 0.87 mmol) in THF (30 mL) was added acetoxyacetyl chloride (119 mg, 0.87 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The obtained solid was washed with diethyl ether-hexane to give the title compound (221 mg, 56%) as a white solid.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:11]2[CH:12]=[C:13]([CH3:44])[C:14]3[N:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:16]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]([O:38]C(C)(C)C)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:15]=3[CH:43]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:11]2[CH:12]=[C:13]([CH3:44])[C:14]3[N:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:16]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]([OH:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][CH:25]=4)[C:15]=3[CH:43]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCN(c1cc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1)S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(c1cc(C)c2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[6-(N-benzenesulphonyl-n-pentylamino)-2-n-butyl-4-methyl-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14](CCC4(C5C=CC=CC=5)CNC4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:30])[N:5]=[CH:4][N:3]=1.S(Cl)(Cl)(=O)=O.C1(S(Cl)(=O)=O)CCCC1.FC1C=C(S(Cl)(=O)=O)C=CC=1.C1C=C(C#N)C(C2OC3N=CC=CC=3N=2)=CC=1.C1(S(Cl)(=O)=O)CC1>>[CH3:30][C:6]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])=[C:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CNC3)CC2C1
Agent: N#Cc1ccccc1-c1nc2cccnc2o1
Agent: O=S(=O)(Cl)C1CC1
Agent: O=S(=O)(Cl)C1CCCC1
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ncnc(C)c1C(=O)N1CC2CNCC2C1

Procedure:
The following were prepared analogously from (4,6-dimethyl-pyrimidin-5-yl)-{5-[2-(3-phenyl-azetidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone using the sulfonyl chloride in parenthesis in place of cyclopentanesulfonyl chloride in the final step: II-2 (m-fluoro-phenylsulfonyl chloride), II-19 (iso-propylsulfonyl chloride) and II-20 (cyclopropyl sulfonyl chloride).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.[NH:24](C(OCC1C=CC=CC=1)=O)[C@H:25]([C:34]([NH:36][C@H:37]([C:41](O)=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[NH2:24][C@@H:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[C:34]([NH:36][C@@H:37]([CH:38]([CH3:39])[CH3:40])[C:41]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:42])=[O:35]
Reactant: CC(C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Method B, Example 12, and employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-Tyr-Val-OH as the starting materials, which yielded the title compound as a white powder. 1H NMR (CD3OD, 300 MHz): δ 7.06 (d, 2H), 6.75 (d, 2H), 4.15-4.06 (m, 2H), 3.18-3.10 (m, 2H), 3.0-2.9 (m, 1H), 2.09-2.02 (m, 1H), 1.92-1.88 (m, 2H), 1.86-1.61 (m, 6H), 1.56-1.50 (m 3H), 1.30-1.17 (m, 4H), 1.06-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 41.72. LCMS m/z: [M+H]+=498.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) in dimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silysia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2c(C(N)=O)[nH]c3ncccc23)cc1

Procedure:
50 mg of solid beige-coloured 3-{4-[3-(2-methoxy-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-methoxy-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: CC(C)[C@@H]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])C(OC)=O.BrC1C=C2C(=CC=1)C(=O)N([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>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].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[CH2:16][N:8]1[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]
Reactant: CCOC(=O)CCN1Cc2cc(Br)ccc2C1=O
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 378 was prepared analogous to compound of example 360 by reaction of the compound of example 377, compound of example 357 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)CN
Reactant: O=C(CBr)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)CNCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To an ice-cooled solution of benzyl bromoacetate (17.1 g, 74.6 mmol) in toluene (200 ml) was added isobutylamine (14.8 ml, 150 mmol) with stirring. The reaction mixture was allowed to warm to room temperature then heated at reflux for 1.5 h before leaving to cool to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (anhydrous MgSO4), filtered and evaporated to an oil which was purified further by column chromatography (silica gel, 25% ethyl acetate in hexane) to give the title compound as a yellow oil (8.96 g, 54%). 1H-NMR; δ(CDCl3), 7.35 (5H, m), 5.18 (2H, s), 3.45 (2H, s), 2.41 (2H, d, J=6.8 Hz), 1.74 (2H, m) and 0.92 (6H, d, J=6.8 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:22])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][C:6]([CH3:22])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1(C)CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CCN(c2ccc(C(C)(C)C)cc2)CC1
Temperature: 90 °C

Procedure:
1-(4-Tert-butyl-phenyl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (155 mg, 0.62 mmol, prepared in accordance with Example 50 without any further purification) was diluted in methanol (4 mL). An aqueous sodium hydroxide solution was then added (2 mL, 4M, 8.00 mmol). The resulting mixture was heated to 90° C. and then maintained at that temperature for 1 hr. After cooling to room temperature, the mixture was filtered. The filtrate was diluted with water (10 mL), and the aqueous phase was washed with ethyl acetate (10 mL). The aqueous phase was then acidified to a pH of 4 with 1 M HCl and extracted with ethyl acetate (2×10 mL). The organic layer was collected, dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a solid (81 mg, 48% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C@:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][N:33]=[CH:32]1.CC(C)([O-])C.[Li+].[Cl-].[NH4+]>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>[Si:24]([O:23][CH2:22][C@:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[O:31][CH:35]=[CH:34][N:33]=5)=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
Reactant: c1cocn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5ncco5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A solution of the compound (800 mg, 1.57 mmol) obtained in Example 52-1), oxazole (217 mg, 3.15 mmol), tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol), and lithium tert-butoxide (260 mg, 3.15 mmol) in dioxane (12 mL) was stirred for 2 h with heating to reflux. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (674 mg, 86%) in a yellow oily form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.CCOCC>O1CCOCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[C@H:37]([CH3:38])[CH2:36][C@@H:35]([OH:39])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
The tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (2.50 g, 4.48 mmol) was dissolved in dioxane (22.4 mL) and treated with 4M HCl in dioxane (22.4 mL, 89.6 mmol) at room temperature. The resulting solution was allowed to stir overnight to completion by LCMS analysis of the crude. The solution was concentrated in vacuo to afford a gel that was dissolved in a minimal amount of methanol (10 mL). The solution was transferred via pipette to stirred ether (300 mL) to afford a white precipitate of desired product. The addition was about half when the white precipitate melted into a yellow gel. The material was concentrated in vacuo to afford a yellow gel which was allowed to stand under reduced pressure overnight to yield (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride as a light yellow powder (2.14 g, 90%).