Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:26])[NH:15][C:16]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Br:25])[CH:17]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[N:27]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]([C:41]([NH2:43])=[O:42])[CH:31]=1)=C=O>O1CCOCC1>[Br:25][C:18]1[CH:19]=[C:20]([CH:21]=[C:16]([NH:15][C:14]([C@@H:13]2[CH2:12][C@@H:11]3[C@@H:9]([CH2:10]3)[N:8]2[C:6](=[O:5])[NH:27][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=3)[N:32]([C:41](=[O:42])[NH2:43])[CH:31]=2)=[O:26])[CH:17]=1)[C:22]([OH:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1
Reactant: COc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1)cn2C(N)=O

Procedure:
The title compound (White solid) was prepared according to the general procedure described in Scheme D5 (Steps B and C) using (1R,3S,5R)-3-(3-bromo-5-carboxy-phenylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester) (prepared by using similar protocols as described in Scheme B7, except that the reaction mixture was heated at 65° C. in step A and dioxane was used instead of MeOH in step B) and 3-Isocyanato-5-methoxy-indole-1-carboxylic acid amide (prepared as described in Scheme A1). MS (LC/MS): 556.0 [M+H]+; tR (HPLC conditions c): 4.32 min.
Reaction SMILES: C(N1CCOCC1)C.[NH:9]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:10]([C:18]([O:20]N1C(=O)CCC1=O)=O)[C@@H:11]([CH3:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[NH2:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[NH:9]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@H:10]([C:18]([NH:38][C@H:39]([C:46]([OH:48])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:20])[C@@H:11]([CH3:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC[C@H](N)C(=O)O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
12.8 ml (0.1 mol) of N-ethylmorpholine and 40.6 g (0.1 mol) of Z-Thr(But)-OSu (Hoppe Seyler's Z.Physiol. Chem. 346, page 60, (1966)) were added at 0° C. to a suspension of 16.1 g (0.1 mol) of H-Ser(But)-OH (Chem. Ber. 97, page 2490 (1964)) in 100 ml of dimethylformamide, the mixture was stirred for 5 hours at room temperature and left to stand at room temperature overnight. When no H-Ser(But)-OH could be detected by thin layer chromatography, undissolved matter, if any, was filtered off, the filtrate was concentrated and the residue was partitioned between ether and 110 ml of 1 N citric acid. The ethereal phase was washed once again with 100 ml of 0.5 N citric acid and then washed neutral with water or NaCl solution. The ethereal phase was dried over Na2SO4, concentrated and dried in a high vacuum. Yield 32.5 g of an amorphous product (72%).
Reaction SMILES: [Cl-].[CH:2]1([NH2+:10][CH2:11][CH2:12]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[S:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]1[N:10]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:11][CH2:12][S:24]1
Reactant: ClCC[NH2+]C1CCCCCCC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2C2CCCCCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][O:10]C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10]
Reactant: COC=Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=CCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A mixture of 1-chloro-2-(2-methoxyvinyl)benzene (2.4 g, 14 mmol) in a solution of 4.0M hydrogen chloride in 1,4-dioxane (36 mL) was stirred for 30 minutes at room temperature. The reaction mixture was then diluted with diethyl ether (100 mL) and treated with saturated aqueous sodium bicarbonate solution (60 mL)—caution: gas evolution. The organic layer was separated, washed with a sodium phosphate buffer (1.0M solution in water, pH=8, 2×40 mL), dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a colorless oil (2.0 g, 90%), which was used in the next step without further purification.
Reaction SMILES: C[O:2][CH:3]=[C:4]1C(=O)OC(C)(C)O[C:5]1=O.[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C(OCC)C>C1C(Cl)=CC=C(Cl)C=1>[Br:14][C:15]1[CH:16]=[C:17]2[C:19]([C:3]([OH:2])=[CH:4][CH:5]=[N:18]2)=[CH:20][C:21]=1[F:22]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: Clc1ccc(Cl)cc1
Solvent: CCOCC
Product: Oc1ccnc2cc(Br)c(F)cc12
Temperature: 200 °C
Yield: 47.9 %

Procedure:
A glass microwave vial was charged with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Bionet; 0.102 g, 0.552 mmol) and 3-bromo-4-fluoroaniline (Matrix Scientific; 0.100 g, 0.526 mmol) in dichlorobenzene (1.00 ml). The reaction mixture was stirred and heated under microwave irradiation (Biotage AB, Inc., Upssala, Sweden) at 200° C. for 10 min. Diethyl ether was added to the reaction and the solids were filtered, washing well with ether (some product passed through with the filtrate) to yield 61 mg of crude 7-bromo-6-fluoroquinolin-4-ol. Material carried forward without further purification. m/z (ESI) 243.9 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.Br[CH2:30][CH2:31][CH:32]=[CH2:33]>>[CH2:33]([O:27][C:21]1[CH:20]=[C:19]([C:16]2[O:17][CH:18]=[C:14]([CH2:13][CH2:12][C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][CH2:2][F:1])=[O:28])[N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26])[CH2:32][CH:31]=[CH2:30]
Reactant: C=CCCBr
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)cc1O
Product: C=CCCOc1cc(-c2nc(CCC(=O)c3ccccc3OCCF)co2)ccc1OC

Procedure:
Using the compound obtained in Example 271 and 4-bromo-1-butene, white powdery 3-[2-(3-but-3-enyloxy-4-methoxyphenyl)oxazol-4-yl]-1-[2-(2-fluoroethoxy)phenyl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.C1(CC([O:36][C:37]2[CH2:46][CH:45]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=O)C=CC=CC=1.[OH-].[K+]>C(O)(C)C.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH:47]1([C@@H:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:38][C@H:37]([OH:36])[CH2:46]2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: O=C(Cc1ccccc1)OC1=Cc2ccccc2C(C2CCCCC2)C1
Agent: Cl[Ru]Cl
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Solvent: c1ccccc1
Product: O[C@H]1Cc2ccccc2[C@@H](C2CCCCC2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
(Peach, P, Cross D J, Kenny J A, Mann I, Houson I, Campbell L, Walsgrove T, and Wills M (2006) Asymmetric transfer hydrogenation of a,3-unsaturated, a-tosyloxy and a-substituted ketones. Tetrahedron 62:1864-1876), (Alcock N J, Mann I, Peach P, and Wills M (2002) Dynamic kinetic resolution-asymmetric transfer hydrogenation of 1-aryl-substituted cyclic ketones. Tetrahedron:Asymmetry 13:2485-2490), (Mogi M, Fuji K, and Node M (2004) Asymmetric reduction of methoxy substituted 3-tetralones using transfer hydrogenation. Tetrahedron:Asymmetry 15:3715-3717) Benzeneruthenium(II) chloride dimer (55 mg, 0.11 mmol) and (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine (80 mg, 11 mmol) were mixed in iso-propanol (25 mL) and heated at 80° C. for 30 min, to generate the catalyst mixture. Separately, 4-cyclohexyl-3,4-dihydronaphthalen-2-yl phenylacetate 1a (950 mg, 2.8 mmol) was heated to 50° C. in iso-propanol (25 mL). Nitrogen gas was used to push the catalyst mixture through a double ended needle to the flask containing 1a, directly followed by a mixture of KOH (0.5 g) in iso-propanol (50 mL). After 3 hours, the reaction was filtered through a pad of silica gel on Celite and then concentrated under reduced pressure. The crude material was purified by column chromatography (Si-gel) to give 2a in a 40% yield.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>C(Cl)Cl>[F:36][C:35]([F:37])([F:38])[O:34][C:31]1[CH:30]=[CH:29][C:28]([NH:25][C:26](=[O:27])[NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:2])=[O:24])[CH2:6][CH2:7]4)=[CH:12][CH:13]=3)=[N:18][CH:19]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(O)CC1CCC(c2ccc(-c3ccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 25 °C

Procedure:
To 150 mg (0.5 mmol) {4-[4-(5-Amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester in 5 mL DCM, 102 mg (0.5 mmol) 1-Isocyanato-4-trifluoromethoxy-benzene was added and the resulting mixture was stirred at room temperature over night. Dilution of reaction mixture with hexanes caused desired product to precipitate which was collected by filtration to afford [4-(4-{5-[3-(4-Trifluoromethoxy-phenyl)-ureido]-pyridin-2-yl}-phenyl)-cyclohexyl]-acetic acid methyl ester: M+1=528.2. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.09-1.20 (m, 2H) 1.50 (td, J=112.63, 10.11 Hz, 2H) 1.80 (s, 3H) 1.83 (d, J=3.28 Hz, 2H) 2.25 (d, J=6.82 Hz, 2H) 2.51-2.54 (m, 1H) 3.61 (s, 3H) 7.31 (dd, J=8.72, 3.16 Hz, 4H) 7.55-7.61 (m, 2H) 7.86 (d, J=8.59 Hz, 1H) 7.94 (d, J=8.34 Hz, 2H) 8.02 (dd, J=8.72, 2.65 Hz, 1H) 8.66 (d, J=2.78 Hz, 1H) 8.99 (s, 1H) 9.05 (s, 1H).
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:30]1SC2C=C(C)C=CC=2N=1>>[CH3:30][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Cc1ccc2nc(Cl)sc2c1
Product: Cc1ccc2nc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)sc2c1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2-chloro-6-methyl-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.31 (m, 4H), 3.12 (q, J=10.6 Hz, 2H), 3.42 (d, J=12.4 Hz, 2H), 4.47-4.57 (m, 1H), 7.41 (d, J=6.9 Hz, 1H), 7.96-8.02 (m, 2H), 8.05 (s, 1H), 8.31 (br. s., 1H), 8.38 (s, 1H), 8.49 (d, J=2.2 Hz, 1H). MS (ES+): m/z=391.15 [MH+]. HPLC: tR=2.22 min (ZQ2, polar—5 min).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:12][CH:11]=1)=[O:8])C>CO.O.Cl>[N:16]1([C:13]2[CH:12]=[CH:11][C:10]([N:9]3[CH:4]=[CH:5][NH:6][C:7]3=[O:8])=[CH:15][CH:14]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CCOC(CNC(=O)Nc1ccc(-n2cncn2)cc1)OCC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.5 %

Procedure:
1-(2,2-Diethoxyethyl)-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]urea (14.5 g) was dissolved in a mixture of methanol (214 ml) and water (85 ml), to which diluted hydrochloric acid (0.48 M, 104 ml) was added dropwise. After the reaction solution was stirred at room temperature for 14 hours, the precipitated crystals were collected by filtration to give 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2-(1H,3H)-imidazolone (8.0 g) as a colorless crystalline powder. The filtrate was concentrated under reduced pressure to about 200 ml and the precipitated crystals were collected by filtration to give an additional amount (1.08 g) of the product.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]3[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:34]([CH2:40][CH2:41][CH3:42])=[N:33][C:27]=3[C:28]([NH2:32])=[N:29][C:30]=2[CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:32][C:28]1[C:27]2[N:33]=[C:34]([CH2:40][CH2:41][CH3:42])[N:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][S:13]([CH2:12][CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)(=[O:15])=[O:14])=[CH:31][C:30]=2[N:29]=1
Reactant: CCCc1nc2c(N)nc3cc(OCCCN)ccc3c2n1CC(C)C
Reactant: O=S(=O)(Cl)CCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(OCCCNS(=O)(=O)CCc4cccc5ccccc45)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
2-(1-Naphthyl)ethanesulfonyl chloride (0.358 g, 1.40 mmol) was added in one portion to a suspension of 7-(3-aminopropoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.41 mmol) in chloroform, and the reaction was stirred for 30 minutes. Triethylamine (0.250 mL, 1.79 mmol) was then added. The reaction mixture was poured into saturated aqueous sodium carbonate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 94:6) and subsequent recrystallization from acetonitrile to yield 0.341 g of N-(3-{[4-amino-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}propyl)-2-(1-naphthyl)ethanesulfonamide as white crystals, mp 164-168° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>C(O)C>[CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1-c1ccnn1C(C)C
Temperature: 55 °C
Yield: 94 %

Procedure:
To a solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole, from Example 1.81, Step C (0.57 g, 2.18 mmol) in ethanol (5.0 mL), was added SnCl2.2H2O (1.97 g, 8.74 mmol) and the mixture was heated at 55° C. overnight. The ethanol was evaporated and the residue was taken in ethyl acetate (50 mL) and washed with 10% NaOH (10 mL). The organic layer was dried over MgSO4 and evaporated to yield a light yellow solid. The crude material was purified via Biotage silica chromatography (hexane/EtOAc, 3/1) to yield a pale yellow solid of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.465 g, 94%). LCMS m/z (%)=232 M+H+ (100), 1H NMR (400 MHz, CDCl3) δ: 7.47 (s, 1H), 6.78 (d, J=8.08 Hz, 1H), 6.72 (dd, J1=8.01 Hz, J2=2.78 Hz, 1H), 6.54 (d, J=2.78 Hz, 1H), 6.25 (s, 1H), 4.14 (m, 1H), 3.63 (s, 3H), 1.4 (d, J=6.57 Hz, 3H), 1.23 (d, J=6.57 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=S)[CH2:20][C:21](=O)[CH3:22])=[O:4].[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][NH2:33])[CH:29]=[CH:28][N:27]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19]1[N:32]([C:30]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:25])[CH:31]=2)[N:33]=[C:21]([CH3:22])[CH:20]=1)=[O:4]
Reactant: NNc1ccnc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-benzenesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 261d) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as yellow solid. MS (ESI): m/z=461.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:29][CH2:28]3)[CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:48]=[CH:47][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:48][CH:47]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:26][CH2:25][CH:24]([CH:27]2[CH2:29][CH2:28]2)[CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccc(OCCc2ccc(F)cc2)cc1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.2 %

Procedure:
The Pd(Ph3P)4 (61.8 mg, 0.053 mmol) was added to a nitrogen purged and degassed solution of (2S)-isopropyl 2-(5-bromo-4-(3-cyclopropylpyrrolidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (125 mg, 0.27 mmol), (4-(4-fluorophenethoxy)phenyl)boronic acid (77 mg, 0.29 mmol), and potassium phosphate tribasic (397 mg, 1.9 mmol) in 1,4-dioxane (3.5 mL) and water (0.9 mL). The reaction mixture was stirred in a screw-capped pressure vessel for 4 h at 90° C., cooled, diluted with EtOAc, and the organic layer was washed with brine and dried (Na2CO3). The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-65% EtOAc/hexanes) using an Isolera chromatography station gave (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 80 mg (49.6%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.21-7.20 (m, 1H), 7.15-7.12 (m, 2H), 7.03-6.94 (m, 3H), 5.77/5.75 (s, 1H), 4.96-4.91 (m, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.17-3.13/3.01-2.97 (m, 1H), 3.05 (t, J=6.6 Hz, 2H), 2.84-2.74 (m, 2H), 2.70-2.67/2.63-2.60 (m, 1H), 2.42/2.41 (s, 3H), 2.07/2.05 (s, 3H), 1.71-1.64 (m, 1H), 1.42-1.22/1.03-0.097 (m, 2H), 1.19-1.17 (m, 3H), 1.14-1.10 (m, 12H), 0.52-0.47 (m, 1H), 0.32-0.23 (m, 2H), −0.30-0.15 (m, 2H). UPLC (M+H)=603.5.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH:25]1([CH2:24][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:21])([F:22])[F:9])=[CH:16][CH:15]=2)[C:18]([OH:20])=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31 M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethyl-phenyl)-acetic acid (693 mg, 3.4 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 30 min. Iodomethylcyclopentane (784 mg, 3.7 mmol) was then added in hexamethylphosphoramide (1 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (10 mL). The excess solvent was removed in vacuo. The residue was acidified to pH=1 with a 1 N aqueous hydrochloric acid solution. The mixture was then poured into water (150 mL) and extracted with ethyl acetate (3×100 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethyl-phenyl)-propionic acid (634.9 mg, 65%) as a white solid: mp 94-95° C.; EI-HRMS m/e calcd for C15H17F3O2 (M+) 309.1079, found 309.1072.
Reaction SMILES: C([O-])(=O)C.[NH4+].C([BH3-])#[N:7].[Na+].[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](=O)[CH3:19])=[CH:14][CH:13]=1)#[N:11]>CO>[C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([NH2:7])[CH3:19])=[CH:14][CH:13]=1)#[N:11]
Reactant: [BH3-]C#N
Reactant: CC(=O)COc1ccc(C#N)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)COc1ccc(C#N)cc1
Yield: 27.8 %

Procedure:
293 g of ammonium acetate and 16.7 g of sodium cyanoborohydride were added to a solution containing 66.5 g of 4-cyanophenoxyacetone dissolved in 1500 mL of methanol, and the resultant mixture was stirred for 30 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and acidified with concentrated hydrochloric acid. 500 mL of diethyl ether and 300 mL of water were then added thereto. Subsequently, the resultant water layer was made basic with a 5% aqueous solution of sodium hydroxide, the solution was extracted with 1000 mL of diethyl ether, and then washed with water. The organic layer was then dried over anhydrous sodium sulfate, and the diethyl ether was removed under reduced pressure. The obtained residue was distilled under reduced pressure to yield 13.0 g of the desired product (19%). Boiling point: 132° C./0.26 mmHg.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[N:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C>CCOC(C)=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[N:36]=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccnc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccnc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 73.4 %

Procedure:
The title compound was prepared from methyl 2-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)nicotinate (30 mg, 0.059 mmol) following General Procedure C. Flash chromatography (10-30% EtOAc) yielded the title compound as a white solid (17 mg, 73%): 1H NMR (CDCl3, 500 MHz) δ 8.85-8.84 (m, 1H), 8.10 (dd, 1H, J=8.0, 1.5 Hz), 7.94 (s, 1H), 7.49-7.47 (m, 1H), 7.36-7.33 (m, 2H), 7.26-7.25 (m, 3H), 4.07 (s, 3H), 3.17 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.88-1.82 (m, 2H), 1.75-1.69 (m, 2H), 1.53-1.47 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 188.5, 167.6, 152.3, 151.8, 144.3, 143.1, 137.7, 129.5, 128.8, 128.7, 127.5, 126.0, 123.9, 53.7, 39.5, 36.3, 31.7, 29.4, 29.4, 24.2; MALDI-FTMS m/z 393.1799 (M+H+, C23H25N2O4, requires 393.1809).