Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=1)[CH2:22][C:23]([O:25]C)=[O:24])=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.[Li+].[OH-].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.O>[C:23]([CH2:22][C@H:21]([NH:20][C:18](=[O:19])[NH:17][C@@H:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:34])=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([I:33])[CH:28]=1)([OH:25])=[O:24]
Reactant: COC(=O)CC(NC(=O)NC(CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1cccc(I)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(O)CC[C@H](NC(=O)N[C@@H](CC(=O)O)c1cccc(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To a solution of (±)2-{3-[1-(3-Iodo-phenyl)-2-methoxycarbonyl-ethyl]-ureido}-pentanedioic acid di-tert-butyl ester (289 mg, 0.49 mmol) was dissolved in methanol (3 mL) and 2M LiOH (0.5 mL) was added and the reqaction stirred at room temperature overnight. The reaction was diluted with water (20 mL) and the organic layer was extracted with ethyl acetate (2×20 mL) then acidified with 1N HCl to pH˜2. The aqueous layer was extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to afford the crude product (206 mg, 0.36 mmol, 73%) as a white solid. To the crude material was added DCM (2 mL) followed by TFA (2 mL) and the reaction was stirred at room temperature overnight. Concentration followed by recrystallization from ethyl acetate afforded the desired product (22 mg, 0.047 mmol, 10%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (br, 3H), 7.64 (br, 1H), 7.56 (m, 1H), 7.30 (bm, 1H), 7.10 (bm, 1H), 6.72 (bm, 1H), 6.34 (bm, 1H), 4.94 (br, 1H), 4.03 (bm, 1H), 2.64 (br, 2H), 2.20 (br, 2H), 1.86 (br, 1H), 1.71 (br, 1H). ESMS m/z: 463 (M−H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[C:21]([Cl:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=1>>[Cl:30][C:21]1[C:20]([CH2:19][O:17][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:11][C:2]([CH3:1])=[N:3]3)=[CH:8][CH:7]=2)=[CH:25][CH:24]=[C:23]([C:26]([F:27])([F:28])[F:29])[N:22]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: FC(F)(F)c1ccc(CBr)c(Cl)n1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccc(C(F)(F)F)nc3Cl)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-bromomethyl-2-chloro-6-trifluoromethyl-pyridine, whereby the product was isolated as free base, 7-(2-chloro-6-trifluoromethyl-pyridin-3-ylmethoxy)-2-methyl-4-pyrrolidin-1-yl-quinoline as a white solid. ISP mass spectrum, m/e: 422.2 (M+1 calculated for C21H19CIF3N3O: 422).
Reaction SMILES: CI.[CH:3]1[C:19]2[C:18]3CC4[C:15]5[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=5[CH:13]=[CH:12][C:11]=4[C:10]=3[CH:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].CS(C)=O>O>[CH3:24][C:25]1([CH3:28])[C:18]2[C:19]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[CH:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]3[CH:15]=[CH:20][CH:21]=[CH:22][C:23]=3[C:26]1=2
Reactant: c1ccc2c3c(ccc2c1)-c1ccc2ccccc2c1C3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CI
Product: CC1(C)c2c(ccc3ccccc23)-c2ccc3ccccc3c21
Reaction time: 10 h
Yield: 58.7 %

Procedure:
Methyl iodide 9.88 g (69.6 mmol) was dropwise added to a mixed solution of 6.18 g (23.2 mmol) of 13H-dibenzo[a,i]fluorene, 11.72 g (104.4 mmol) of potassium t-butoxide and 100 ml of dimethylsulfoxide at 20° C. in 20 minutes, and the solution was stirred for 10 hours. After left standing overnight, 9.88 g (69.6 mmol) of methyl iodide was further dropwise added and stirred for 5 hours. Water was dropwise added to the reaction mixture, and the solution was extracted with dichloromethane. After separating the solution, the organic phase was concentrated and refined by flash chromatograph (silica gel: hexane/dichloromethane=5/1) to obtain 4.01 g (yield: 58.7%) of 13,13-dimethyl-13H-dibenzo[a,i]fluorene.
Reaction SMILES: C(=O)([O-])O.[K+].Cl.[NH2:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:15])[NH2:14].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].Cl.[Cl-].[Na+]>O.CC(C)=O>[C:19]([NH2:7])(=[O:23])[C:20]([CH3:22])=[CH2:21].[NH2:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[NH:14])[NH2:15]
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(N)=O

Procedure:
Potassium hydrogencarbonate(27.64 g) was dissolved in 200 ml of distilled water, 21.07 g of arginine hydrochloride was dissolved in the solution, and 80 ml of acetone was further added to the solution. The reaction mixture was added dropwise with 10.46 g of methacryloyl chloride over about 10 minutes with vigorous stirring under ice cooling, and further vigorously stirred for 1 hour. The reaction mixture was adjusted to pH 1 with concentrated hydrochloric acid, and saturated with sodium chloride. The aqueous layer was washed 3 times with 300 ml of ethyl acetate, and extracted 3 times with 200 ml of ethyl acetate/isopropanol =1/1. The ethyl acetate/isopropanol layers were combined, concentrated to about 100 ml under reduced pressure, added with 400 ml of isopropanol, and again concentrated to about 200 ml. The deposited sodium chloride was removed by filtration, and the filtrate was concentrated (colorless syrup, 21.80 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].S(O[CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]=[CH:26][O:25]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:23][CH:24]1[CH2:29][CH2:28][CH:27]=[CH:26][O:25]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Yield: 76.1 %

Procedure:
A solution of 359 mg of 2,4-dichlorophenol in 3 ml of dimethylformamide was stirred with 96 mg of 55% sodium hydride at room temperature for 30 minutes. A solution of 536 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 2 ml of dimethylformamide was then added, and the mixture was heated at 80°-90° C. for 2 hours. The reaction mixture was then cooled and poured onto a mixture of ice and sodium bicarbonate. The mixture was extracted with diethyl ether and the extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the residue was purified by column chromatography through silica gel eluted with a 1:2 by volume mixture of benzene and hexane, to give 394 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:18](O)([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(S(F)(F)[F:34])CC>ClCCl>[CH:1]1([C:4]2[C:5]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:18]([F:34])([CH3:20])[CH3:19])[C:14]([NH:16][CH3:17])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of 5-cyclopropyl-N-[3-hydroxy-3-methyl-1-(methylamino)-1-oxobutan-2-yl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 236b, 75 mg, 193 μmol) in dry dichloromethane (2 ml) under an argon atmosphere was added DAST (38.8 mg, 31.8 μl, 241 μmol). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with a 1M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (25 mg, 33%). MS (ESI, m/z): 392.6 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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(O)C>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1

Procedure:
10 g (42.2 mmol) of 2,5-dibromopyridine, 5.2 g (42.2 mmol) of phenylboronic acid and 30 ml of benzene are placed in a 250 ml three-necked round-bottomed flask, 1.5 g (1.3 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of benzene and 30 ml of aqueous 2 M sodium carbonate solution and 1.4 ml of ethanol are added and the mixture is refluxed for 17 h.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:17]([CH:18]=O)=[CH:16][C:11]3[C:12]([CH3:15])=[N:13][O:14][C:10]=3[C:9]=2[F:20])[CH2:5][C@H:4]([CH3:21])[O:3]1.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>C(O)(C)C.CO>[F:20][C:9]1[C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=[C:17]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:21])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:18]2
Reactant: Cc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(C)O
Solvent: CO
Product: Cc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
To a stirred solution of 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 34, 543 mg, 1.86 mmol) in isopropanol (50 ml) was added pyrimidine-2,4,6(1H,3H,5H)-trione (238 mg, 1.86 mmol), and the reaction mixture was stirred for 16 hours at 80° C. Solvent was removed and the residue was triturated with isopropanol. The solid was filtered, washed with isopropanol, and dried in vacuo. The filtrate was concentrated and purified on silica gel (30-50% EtOAc in hexanes). The product thus obtained was combined with the filtered solid in methanol and concentrated to give the title compound (528 mg, 71%) as a racemic mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH2:21]([O:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][N:37]([C:38]([C:40]3[CH:45]=[C:44](Cl)[N:43]=[CH:42][N:41]=3)=[O:39])[C:32]2=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:21]([O:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][N:37]([C:38]([C:40]3[N:41]=[CH:42][N:43]=[C:44]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:45]=3)=[O:39])[C:32]2=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2nc(OCc3ccccc3)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)n4ccc5nc(OCc6ccccc6)ccc54)ncn3)CC1)C(=O)N2
Reaction time: 0.5 h

Procedure:
0.11 g (0.40 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.14 g (0.38 mmol) (5-benzyloxy-pyrrolo[3,2-b]pyridin-1-yl)-(6-chloro-pyrimidin-4-yl)-methanone and 0.10 mL (0.58 mmol) DIPEA in 5 mL DMF were stirred overnight at RT. The reaction mixture was diluted with water and stirred for 30 min. The precipitate formed was suction filtered, washed with water and MeOH and dried.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]3[CH2:22][C@@H:21]([C:23](=[O:35])[NH:24][C@H:25]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][CH2:27][CH2:26]4)[N:20]([C:36](=[O:58])[C@@H:37]([NH:44][C:45](=[O:57])[C@@H:46]([N:48]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH3:49])[CH3:47])[CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:19]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[C:53]([O:52][C:50](=[O:51])[N:48]([C@H:46]([C:45](=[O:57])[NH:44][C@@H:37]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[C:36]([N:20]1[CH2:19][C@@H:18]([NH2:17])[CH2:22][C@H:21]1[C:23](=[O:35])[NH:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:58])[CH3:47])[CH3:49])([CH3:54])([CH3:55])[CH3:56]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
{(3S,5S)-1-{(S)-2-[(S)-2-(tert-Butoxycarbonyl-methyl-amino)-propionylamino]-2-cyclohexyl-acetyl}-5-[(R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)carbamoyl]-pyrrolidin-3-yl}-carbamic acid 9H-fluoren-9-ylmethyl ester (Intermediate 25) (100 mg, 124 μM) was dissolved in DMF (0.9 mL) at room temperature and piperidine (0.1 mL) was added. The mixture was stirred at room temperature for 30 minutes, concentrated and the residue purified by chromatography over silica gel to give the title compound as white foam (56.7 mg, 78%). LC-MS: 585 (M+H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[N:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.9 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide (0.36 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH, dichloromethane) yielded the title compound as a white solid (0.11 g, 21%). MS (ISP) 514.2 [(M+H)+]; mp 269.5° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]3[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>[Cu]I>[CH3:29][C:30]1[CH:31]=[N:32][N:33]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C@@H:15]4[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]4[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=1
Reactant: Cc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(I)cc2)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Product: Cc1cnn(-c2ccc(N3CCC[C@H](N[C@@H]4CCCC[C@H]4NC(=O)OC(C)(C)C)C3)cc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a sealed tube was added tert-butyl (1R,2R)-2-((S)-1-(4-iodophenyl)piperidin-3-ylamino)cyclohexylcarbamate (150 mg, 0.300 mmol), 4-methyl-1H-pyrazole (29.6 mg, 0.360 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (8.54 mg, 0.060 mmol), K2CO3 (87 mg, 0.631 mmol) and copper(I) iodide (5.72 mg, 0.030 mmol). The reaction was bubbled with argon for 2 min. The reaction vessel was sealed and the reaction was stirred at 100° C. for 16 hrs. After this time, the reaction was cooled to rt and diluted with water. The layers were separated and aqueous solution was extracted with EtOAc (2×30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 20-100% EtOAc/Hex to give tert-butyl (1R,2R)-2-((S)-1-(4-(4-methyl-1H-pyrazol-1-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate (86 mg, 0.190 mmol, 63.1% yield). Anal. Calcd. for C26H39N5O2 m/z 453.5, found: 454.4 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:11][C:12]1[C:13]([Cl:20])=[CH:14][C:15]([CH2:18]Cl)=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.CS(C)=O>[CH2:4]([O:11][C:12]1[C:13]([Cl:20])=[CH:14][C:15]([CH2:18][O:2][CH3:1])=[N:16][CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[O-]
Reactant: ClCc1cc(Cl)c(OCc2ccccc2)cn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COCc1cc(Cl)c(OCc2ccccc2)cn1
Temperature: 100 °C
Yield: 91 %

Procedure:
A solution of 9.30 g (172 mmol) of sodium methylate in 132 ml methanol was added drop wise to a solution of 5-benzyloxy-4-chloro-2-chloromethyl-pyridine (Australian Journal of chemistry, 1977, 30, 649) in 130 ml DMSO. The suspension was heated at 100° C. for 6 h, poured on ice, extracted with four portions of CH3Cl. The organic phases were dried (Na2SO4), evaporated and distilled (Kp 0.2 mm Hg, 150-152° C.) to give 12.80 g (91%) of the title compound. MS: 264.0 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([C:14](C)(C)[O:15][SiH2]C(C)(C)C)([F:13])[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:13])([CH2:14][OH:15])[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@](F)(C(C)(C)O[SiH2]C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CO)C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4R)-4-(tert-butyl-dimethyl-silanyloxymethyl)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (4.10 g, 8.77 mmol) in THF (80 mL) at RT was added 1M TBAF in THF (17.53 mL, 17.53 mmol). The reaction was stirred at RT for 30 min then poured into water and extracted with EtOAc. The organic layer was dried with Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (c-hexane/EtOAc 3:2). MS (UPLC/MS): 354 [M+H]+, 398 [M+HCOO]−; tR (HPLC conditions f): 2.07 min.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13]Br)[CH:8]=2)=[CH:5][CH:6]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[K+]>C(O)(=O)C.O>[C:15]([O:18][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[O:3][C:2]([Br:1])=[CH:6][CH:5]=2)[CH:8]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: BrCc1cccc(-c2ccc(Br)o2)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCc1cccc(-c2ccc(Br)o2)c1
Reaction time: 19 h
Yield: 56 %

Procedure:
A stirred solution of 7.3 g (0.023 mol) of 2-bromo-5-(3-bromomethylphenyl)furan in 50 mL of acetic acid was cooled in an ice-water bath, and 3.4 g (0.035 mol) of potassium acetate was added. Upon complete addition, the reaction mixture was heated to reflux temperature and stirred for 19 hours. The reaction mixture was transferred to a separatory funnel, diluted with 100 mL of water, then extracted with two portions of 150 mL each of chloroform. The combined extracts were washed with one portion of 150 mL of a saturated aqueous solution of sodium chloride, two portions of 150 mL each of a saturated aqueous solution of sodium bicarbonate, and finally with one portion of 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel, eluting with hexane: chloroform (2:1). The appropriate fractions were combined to give 3.8 g of 3-(2-bromo-5-furanyl)phenylmethyl acetate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3=[O:24])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C2C(=C(N3CCN(C(OC(C)(C)C)=O)CC3)C=CC=2)CCN=1>>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][C:12]3=[O:24])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)C(=O)C1
Agent: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN=C3)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN=C3)C(=O)C1

Procedure:
Intermediate 21 was prepared from Intermediate 21A as described for Intermediate 18. MS (ESI) m/z: 330.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[CH:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.[O:26]1CCCC1.C(=O)(O)[O-].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH2:2][CH2:3][OH:26])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=CCNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C1CCOC1
Agent: B
Agent: O=C([O-])O
Agent: OO
Solvent: CCO
Product: O=C(NCCCO)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 12B-e, 132 mg, 0.36 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a 1M solution of borane-tetrahydrofuran (0.7 mL, 0.72 mmol). The reaction mixture was allowed to slowly warm from 0° C. to 25° C. over 1 h. At this time, the solution was re-cooled to 0° C. and ethanol (2 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (6 mL) and 30% hydrogen peroxide (2 mL) was added slowly. This mixture was allowed to slowly warm to 25° C. while stirring for 1 h. At this time, the reaction was re-cooled to 0° C. and slowly quenched with a saturated aqueous sodium sulfite solution (20 mL). This solution was extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×15 mL), dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) effected the separation of two spots, the second of the two product spots to elute off the column afforded 1-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-3-(3-hydroxy-propyl)-urea (73 mg, 53%) as a white hygroscopic solid: EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1172.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:9])[CH3:8])([CH3:5])[CH3:4].N[C:11]1(CO)CCC[CH2:12]1.CC#N.O.CC#N>O>[OH:1][CH2:2][C:3]1([NH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:12][CH2:11][CH2:4]1
Reactant: NC1(CO)CCCC1
Reactant: CC(=O)NC(C)(C)CO
Solvent: O
Solvent: CC#N
Product: CC(=O)NC1(CO)CCCC1

Procedure:
The title compound is prepared analogously as described for N-(2-hydroxy-1,1-dimethyl-ethyl)-acetamide from (1-amino-cyclopentyl)-methanol. MS (LC-MS): [M+H]+=158.2. tR (HPLC, Waters sun fire C18 column, 5-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.8 mL/min): 1.76 min.