Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:35][CH2:34][C@@H:33]([N:36]([CH3:38])[CH3:37])[CH2:32]3)=[O:30])[CH:23]=2)=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:37][N:36]([CH3:38])[C@@H:33]1[CH2:34][CH2:35][N:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[O:30])[CH2:32]1
Reactant: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)nc3)ccn2)C1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.248 g, 2.453 mmol) in DCE (5 mL) was treated with oxalyl chloride (0.197 mL, 2.331 mmol), heated at 100° C. for 1 h, cooled to RT, added drop-wise to a solution of (R)—N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (0.600 g, 1.752 mmol) and pyridine (0.198 mL, 2.453 mmol) in THF (10 mL) and stirred at RT overnight. The mixture was concentrated to dryness, treated with satd. NH4Cl, extracted with EtOAc (4×) and the combined organics were washed with water, dried over Na2SO4 and concentrated to dryness. The residue was suspended in MeCN, sonicated and the resulting solid collected via filtration to afford (R)-3-(dimethylamino)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (280 mg, 34%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (br s, 1H), 8.78 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 8.08 (d, J=8.9 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.62 (m, 1H), 3.52 (m, 1H), 3.27 (m, 1H), 3.08 (m, 1H), 2.65 (m, 1H), 2.15 (s, 6H), 2.08-1.95 (m, 1H), 1.65 (m, 1H), 1.21 (s, 9H); MS (ESI) m/z: 470.3 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>CC(O)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:18]2[C:13]3[C:12]([Br:20])=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CC1
Temperature: -10 °C
Yield: 86.9 %

Procedure:
A suspension of 7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.9 g, 13 mmol), Piperazine-1-carboxylic acid tert-butyl ester (3.7 g, 20 mmol), and DIPEA (5.7 mL, 33 mmol) in IPA (30 mL) was stirred and heated at reflux for 6 hours. The mixture was cooled to −10° C., the solids collected by vacuum filtration, rinsed with cold IPA and dried under vacuum to give 4-(7-Benzenesulfonyl-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (5.9 g, 86%.) LCMS (APCI+) m/z 522 and 524 [M+H]+; Rt: 3.92 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.48 (1H, s), 8.21 (2H, d, J 8.2 Hz), 7.66-7.62 (2H, m), 7.54 (2H, t, J 7.8 Hz), 3.62-3.55 (8H, m), 1.48 (9H, s.)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][S:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH:29]1([CH2:28][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=2)[C:24]([OH:26])=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ICC1CCCC1
Reactant: COCSc1ccc(CC(=O)O)cc1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
A solution of diisopropylamine (0.37 mL, 2.62 mmol) in tetrahydrofuran (2 mL) was cooled to −78° C. and then treated with a 2.5M solution of n-butyllithium in hexanes (1.05 mL, 2.62 mmol). This solution was stirred at −78° C. for 30 min and then treated with a solution of (4-methoxymethylsulfanyl-phenyl)-acetic acid (223 mg, 1.05 mmol) in tetrahydrofuran (1.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL). The reaction mixture was allowed to stir at −78° C. for 1 h. At this time, the reaction was treated with iodomethylcyclopentane (328 mg, 1.56 mmol). The reaction mixture was allowed to slowly warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution and then concentrated in vacuo. The residue was treated with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous layer was then acidified with concentrated hydrochloric acid. This solution was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methoxymethylsulfanyl-phenyl)-propionic acid (202 mg, 65%) as an off-white solid: mp 167-170° C.; EI-HRMS m/e calcd for C16H22O3S (M+) 294.1290, found 294.1288.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.[Cl:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C@H:19]2[CH3:31])=[N:14][CH:15]=[CH:16][N:17]=1>>[ClH:11].[CH3:31][C@@H:19]1[CH2:20][NH:21][CH2:22][CH2:23][N:18]1[C:13]1[C:12]([O:10][CH2:9][CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17][CH:16]=[CH:15][N:14]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Reactant: OCCOc1cccnc1
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1
Product: Cl

Procedure:
The title compound was prepared starting from 2-(3-pyridyloxy)ethanol (from Example 150, Step 1) and 3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine (from Example 172, Step 2). The pure free base was precipitated as its hydrochloride salt with HCl/ether to give the title compound as white crystals: yield 31%; mp 180-183° C.; HRMS m/z calcd for C16H21N5O2 (M)+ 315.1695, found 315.1689. Anal. (C16H21N5O2.1.33HCl) C, H, N.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:38]=[CH:37][C:16]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.[CH3:39][Mg]Br>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:23][CH:24]=2)([OH:18])[CH3:39])=[CH:37][CH:38]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
To a solution of 4,4'-di(2-quinolylmethoxy)benzophenone (992 mg, 2 mmol) in THF (20 mL) at -78° C. was added methylmagnesium bromide (3M solution in ethyl ether, 0.8 mL, 2.4 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The extract was washed with water, brine, dried with anhydrous MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride-ethyl acetate 4:1) to afford 920 mg of 1,1-bis(4-(2-quinolylmethoxy)phenyl)ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: OCCO
Reactant: Cc1ccc(C=O)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2OCCO2)cc1Br
Yield: 89.1 %

Procedure:
11.8 g (60 mmol) of 3-bromo-4-methylbenzaldehyde are placed in 150 ml of toluene in a round-bottomed flask and under nitrogen. 16.5 ml (300 mmol) of ethylene glycol and 571 mg (3 mmol) of para-toluenesulfonic acid are added. The mixture is refluxed for 36 hours and the water formed is separated out using Dean-Stark apparatus. At room temperature, the reaction medium is poured into saturated aqueous sodium hydrogen carbonate solution and then extracted with ether. The organic phase is dried over magnesium sulfate, filtered and evaporated. 13 g (89%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]1[CH2:13][CH2:12]1.[F:14][C:15]([F:22])([F:21])[C@H:16]([OH:20])[CH2:17][CH2:18][OH:19].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[CH:11]1([C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[N:7][C:2]=2[O:20][C@@H:16]([C:15]([F:22])([F:21])[F:14])[CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cl)n1
Reactant: OCC[C@@H](O)C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1
Temperature: 140 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Solvent: O
Product: O=Cc1c(O)cccc1O
Temperature: 65 °C

Procedure:
To 185 g of the dispersion of sulfonated monodisperse seed particles from Example 1, with a solids content equal to 1 g, was added 0.9 l of water, 452 g of resorcinol and 1355 g of 37% formaldehyde solution. The mixture was heated at 65° C. for 2.5 hours under stirring. To isolate the particles the same procedure was followed as in Example 5. The particle size obtained was also in this case 18 μm, reflecting the maximum swelling capacity of the seed particles.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37][SH:38])([CH3:34])[CH3:33]>>[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37][S:38][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)([CH3:34])[CH3:33]
Reactant: CC(C)N(CCS)C(C)C
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: Cl
Product: CC(C)N(CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)C(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-diisopropylaminoethanethiol hydrochloric acid salt.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:11]([CH3:36])[C:10]=1[CH3:37].[F:38]/[C:39](=[CH:48]\[CH:49]=[C:50](/[CH3:53])\[CH:51]=O)/[C:40](/[CH3:47])=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[C:33]([CH3:35])[C:12](/[CH:13]=[CH:53]/[C:50](/[CH3:51])=[CH:49]/[CH:48]=[C:39](\[F:38])/[C:40](/[CH3:47])=[CH:41]/[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:11]([CH3:36])[C:10]=1[CH3:37]
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Temperature: -30 °C

Procedure:
A solution of 6.06 ml. (14.4 mmol) of n-butyllithium (2.3 M in hexane) was added dropwise under argon, at -72° C., to a stirred suspension of 4.61 g. (10 mmol) of 4-methoxy-2,3,6-trimethylbenzyl triphenylphosphonium chloride in 25 ml. of dry tetrahydrofuran. After addition of reagent was complete the mixture was stirred at -30° C. until an orange solution was formed. The resulting solution was first cooled to -72° C. and then treated dropwise with a solution of 2.03 g. (9.0 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 10 ml. of dry tetrahydrofuran. The reaction mixture was gradually allowed to come to 25° C. and further stirred at this temperature under argon for 2.0 hours. It was poured onto 100 ml. of cold water and extracted with methylene chloride (4×100 ml.). The combined organic extracts were washed with water (2×100 ml.) dried over anhydrous magnesium sulfate and concentrated to give 6.4 g. of oily crude product. This material was filtered through 300 g. of florisil and eluted with methylene chloride to yield 2.97 g. of yellow crystalline substance, which on crystallization from ether-petroleum ether (~1:9) afforded ethyl (E,Z,E,E)-9-(4-methoxy-2,3,6-trimethylphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp 92°-96° C.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]([N:14]([CH2:27][CH2:28][CH3:29])[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH2:25][NH2:26])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:12][CH3:13].[OH-].[Na+]>CCOCC.O>[CH2:27]([N:14]([CH2:11][CH2:12][CH3:13])[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH2:25][NH:26][CH:5]=[O:7])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:28][CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: O=CO
Product: CCCN(CCC)C1CCc2cccc(CNC=O)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.04 ml (21.5 mmol) of acetic anhydride and 0.86 ml (22.8 mmol) of formic acid were stirred for 2 h at +60° C. under nitrogen. After cooling to room temperature, 2.6 g (10 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were added dropwise at a maximum of +25° C. After 15 minutes post-reaction, 5 ml of ether were added. The batch was subsequently stirred for a further 18 h at room temperature and then diluted with 20 ml of ether and 20 ml of water. The aqueous phase was adjusted to pH 9 using 1N sodium hydroxide solution and extracted with ether. The organic phase now obtained was washed with water and dried over sodium sulphate, and the solvent was removed by distillation. The residue was recrystallized from petroleum ether 60-80.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:26][CH:27]=[CH2:28])[C:22](OC)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1.CCOC(C)=O>[CH3:4][O:3][P:2]([CH2:1][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:26][CH:27]=[CH2:28])([O:5][CH3:6])=[O:7]
Reactant: COP(C)(=O)OC
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)CP(=O)(OC)OC
Reaction time: 0.67 h
Yield: 88.6 %

Procedure:
To a solution of dimethyl methylphosphonate (13.98 mL, 131 mmol) in THF (87 mL) at −78° C. was added n-BuLi (82 mL, 131 mmol) slowly. After completion of addition, the reaction was stirred for 40 min and then a solution of (S)-methyl 2-(tert-butoxycarbonylamino)pent-4-enoate (6.0 g, 26.2 mmol) in THF (30 mL) was added slowly. Stirring was continued for another 40 min at −78° C. The reaction mixture was then quenched by adding H2O (2.357 mL, 131 mmol). The reaction mixture was diluted with EtOAc (100 mL) and the layers were separated. The organic layer was washed with 1M HCl, saturated NaHCO3 solution followed by brine. The organic phase was then dried over MgSO4, filtered and concentrated to give a clear oil. The crude product was purified using silica gel chromatography to give 5E (7.46 g, 89%) as colorless oil. MS (ESI) m/z: 343.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 5.63-5.76 (1H, m), 5.08-5.17 (2H, m), 4.33-4.43 (1H, m), 3.80 (3H, d, J=2.20 Hz), 3.77 (3H, d, J=2.20 Hz), 3.28-3.37 (1H, m), 3.05-3.16 (1H, m), 2.58-2.69 (1H, m), 2.42 (1H, dt, J=14.58, 7.29 Hz), 1.43 (9H, s).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:8]=1[NH:18]C(=O)OCCCC)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.O1CCOCC1>CO>[NH2:18][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:12][C:7]=1[NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a stirred solution of tort-butyl (2-isobutyramido-4-(thiophen-2-yl)phenyl)carbamate (0.2 g, 0.52 mmol) in methanol (4 mL) was added 4M HCl in Dioxane (2 mL, 0.53 mmol, 1 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. After completion the reaction was concentrated under reduced pressure then basified with a saturated aqueous solution of NaHCO3. The obtained solid was filtered and dried. The crude material was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)isobutyramide (0.05 mg, 36% yield). ESI+ MS: ink 261 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.10 (s, 1H0, 7.5 (s, 1H0, 7.34 (d, J=4.5 Hz, 1H), 7.23-7.19 (m, 2H), 7.05-7.03 (m, 1H0, 6.75 (d, J=8.5 hz, 1H0, 5.03 (s, 2H), 2.67-2.64 (m, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=N[C:42]2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[C:68](CC)[CH:67]=1>C(Cl)Cl>[CH2:41]([NH:72][C:70]([C:69]1[CH:68]=[CH:67][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:29])=[CH:74][CH:73]=1)=[O:71])[CH3:42]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1cc(N)ccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 147 mg, 0.39 mmol) was added followed by the addition of DIPEA (0.225 mL, 1.29 mmol) and 4-amino-ethyl-benzamide (made by reducing the corresponding nitro precursor, 56 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes) to give a white solid. 42 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.CO.[C:26](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:26])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Yield: 75 %

Procedure:
2-(4-Chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (54; 500 mg, 1.46 mmol) was suspended in CH2Cl2 (15 mL). Methanol (2 mL) was added to solubilize. To the reaction solution was added dropwise oxalyl chloride (130 μL, 1.46 mmol). After having stirred the reaction at room temperature overnight, the reaction was concentrated. The residue was taken up in EtOAc and washed successively with saturated NaHCO3 and then brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (EtOAc/pentane) afforded methyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate as an orange solid (structure not shown) (390 mg, yield: 75%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][N:22](CC3C=CC=CC=3)[CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Yield: 69.8 %

Procedure:
To the solution of 5-Phenyl-3-[1-(phenylmethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole-7-carboxamide (2.66 g, 6.5 mmol) in ethanol (150 mL) and acetic acid (3 mL) was added Pd(OH)2 (20% by weight on carbon) (0.8 g,) at ambient temperature. The solution was stirred under 1 atm of hydrogen for 2 days. The reaction mixture was then filtered through Celite, neutralized with 5% sodium hydroxide solution, and extracted with ethyl acetate. The solvent was removed under reduced pressure to yield the desired product (1.45 g, 70%).
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=2[S:6][C:5]=1[S:18][CH3:19])([OH:3])=[O:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].[Na+]>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:2][C:1]([C:4]2[C:9](=[O:10])[C:8]3[CH:11]=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:7]=3[S:6][C:5]=2[S:18][CH3:19])=[O:3])=[CH:24][CH:23]=1
Reactant: CSc1sc2c(F)c(F)c(F)cc2c(=O)c1C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)c2c(SC)sc3c(F)c(F)c(F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a suspension of 50 mg (0.163 mmol) of the compound of Example 112 in 0.2 ml of chloroform were added 30.7 mg (0.196 mmol) of p-methoxybenzyl chloride, 16.5 mg (0.163 mmol) of triethylamine and 29.4 mg (0.196 mmol) of sodium iodide, and the mixture was stirred for 5 hours at room temperature, which was poured into ice-water and extracted with dichloromethane. The organic layer was washed with water and with saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (CHCl3) to obtain 22.5 mg (0.0528 mmol) of title compound (yield 32%).