Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6])[OH:4].[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][C:17]=1Cl>O1CCOCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]2[O:4][C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[O:6][C:16]=2[CH:17]=1
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: Oc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1cc2c(nn1)Oc1ccccc1O2
Yield: 69.7 %

Procedure:
In 1,4-dioxane (30 mL) was suspended 3.49 g (80.0 mmol) of 55% sodium hydride, and to the suspension were added a 1,4-dioxane (30 mL) solution containing 4.40 g (40 mmol) of pyrocatechol, then a 1,4-dioxane (30 mL) solution containing 7.30 g (39.9 mmol) of 3,4,6-trichloropyridazine {described in The Journal of Organic Chemistry, 1963, vol. 28, pp. 218 to 221.}, and the mixture was refluxed for 2 hours. The reaction mixture was poured into ice-cold water, and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L sodium hydroxide and water, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was recrystallized from methyl isobutyl ketone to obtain 6.15 g (27.8 mmol, Yield: 69.7%) of 3-chloro[1,4]-benzodioxino[2,3-c]pyridazine.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.C(=O)([O-])O.[Na+]>ClCCl>[CH3:16][C:8]1[C:7]([OH:6])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2
Reactant: COc1ccc2[nH]ncc2c1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(O)ccc2[nH]ncc12
Reaction time: 1 h
Yield: 40.7 %

Procedure:
A solution of boron tribromide (0.513 ml, 5.43 mmol) in dichloromethane (5 ml) was added dropwise to a solution of the 5-methoxy-4-methyl-1H-indazole (400 mg, 2.47 mmol) obtained in Example 401 in dichloromethane (5 ml) at 0° C. After 1 hour, the reaction solution was poured onto ice (50 ml), adjusted to pH 4 to 5 with a saturated aqueous sodium hydrogencarbonate solution, and then extracted with chloroform (20 ml×2) and ethyl acetate (20 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-methyl-1H-indazol-5-ol (149 mg, 41%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([CH3:33])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([CH3:33])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)c(C2CC2)c1
Yield: 22.9 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (203 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (418 mg) described in Preparation Example 129 and by the reaction and treatment in the same manner as in Example 4, the title compound (108 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(Cl)CCl>C(Cl)Cl>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][NH:27][C:14](=[O:16])[CH:13]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:2]([F:1])[CH:3]=2)[CH3:17])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CC(C(=O)O)c1ccc(NS(C)(=O)=O)c(F)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
A mixture consisting of 2-[3-Fluoro-4-(methylsulfonylamino)phenyl]propionic acid (1-38, 10 mmol), 4-t-butylbenzylamine (12 mmol) and EDC (12 mmol) in CH2Cl2 (20 mL) was stirred for 12 h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated. the residue was purified by flash column chromatography on silica gel using EtOAc:hexanes as eluant to obtain N-(4-tert-butylbenzyl)-2-[3-fluoro-4-(metylsulfonylamino)phenyl]propionamide (1-51, KMJ-372) having following physicochemical properties:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[N+:18]([C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br)([O-:20])=[O:19]>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N+:18]([O-:20])=[O:19])[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1[N+](=O)[O-]

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-nitrobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([O:24][Si:25]([C:28]([CH3:31])([CH3:29])[CH3:30])([CH3:27])[CH3:26])[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(CCCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(CCCc4ccccc4)O[Si](C)(C)C(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 5-(4-bromo-phenyl)-4-[1-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-3-methyl-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:32])[C@@H:10]([NH:14][C:15]([O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:12])[O:13][C@H:9]2[CH3:32])[CH2:19][CH2:20]1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1CCN(C(=O)c2ccccc2)CC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 8.8 %

Procedure:
In a four necked round bottom flask, under Argon atmosphere, Et3N (1.2 mL, 8.56 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-[({[1-(phenylcarbonyl)piperidin-4-yl]oxy}carbonyl)amino]-butanoic acid (1.0 g, 2.85 mmol) in dry CH2Cl2 (40 mL). After cooling at 0° C., HBTU (1.62 g, 4.28 mmol) was added and the mixture stirred 3 h at 0° C., then 16 h at rt. The solvent was removed under vacuum, and the resulting crude mixture was purified by column chromatography using a Teledyne ISCO apparatus, eluting with CH2Cl2/AcOEt (50:50). The resulting yellow solid was further purified trough reverse-phase automatic column chromatography, eluting with H2O/CH3CN (70:30) to afford the title compound (0.083 g, 9%) as white solid. Rf=0.47 (SiO2, CH2Cl2/AcOEt 1:1); Rf=0.39 (C18, 7:3 H2O/CH3CN). MS (ESI) m/z: 333 [M−H]+. FTIR (cm−1): 3414, 3222, 3050, 2965, 2929, 2871, 1825, 1720, 1612, 1550, 1449, 1262, 1232, 1119, 1068, 1031, 837, 711. 1H-NMR (CDCl3): δ 1.47 (d, 3H); 1.58-2.04 (m, 4H); 3.30-4.08 (m, 4H); 4.86-4.90 (m, 1H); 4.93-4.97 (m, 1H); 5.45 (t, 1H); 5.56 (br s, 1H); 7.39-7.44 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][OH:13].[CH:14](O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:14][N:10]([CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(NCCO)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ncn(CCO)c2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((2-amino-5-methoxyphenyl)amino)ethanol (914 mg, 5.01 mmol) in THF (30 mL), formic acid (0.19 mL, 5.01 mmol) was added. After stirring at 80° C. for 30 min the reaction was allowed to reach rt and basified with conc. aq.NaHCO3-solution. The aq. layer was extracted with DCM (5×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 2-(6-methoxy-1H-benzo[d]imidazol-1-yl)ethanol as a brown oil which was used as such in the next step. LC-MS conditions B: tR=0.30 min, [M+H]+=193.13.
Reaction SMILES: [N:1]([CH:4]([CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5])=[N+]=[N-]>CO.Cl.O=[Pt]=O>[NH2:1][CH:4]([CH:6]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(C)CC(c1ccccc1)C(C)N=[N+]=[N-]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CC(C)CC(c1ccccc1)C(C)N
Reaction time: 2 h

Procedure:
To a solution of 32 mg 2-azido-5-methyl-3-phenylhexane in 1 mL MeOH and 2 drops of 1.2 N HCl, 4 mg PtO2 was added and the solution was stirred under H2 atmosphere for 2 h. The reaction was filtered through a pad of CELITE diatomaceous earth and the pad was rinsed with MeOH. The combined filtrate was concentrated to give the desired product. 1H NMR: (500 MHz, CDCl3): δ 0.86 (m, 6H), 0.99 (d, 3H), 1.25 (m, 1H), 1.54 (m, 1H), 1.77 (m, 1H), 2.73 (m, 1H), 3.19 (m, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: Cl.CN.[Cl:4][C:5]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:6]=1[S:13](Cl)(=[O:15])=[O:14].[CH2:17]([N:19](CC)CC)C>ClCCl>[CH3:17][NH:19][S:13]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([CH3:11])[C:5]=1[Cl:4])(=[O:15])=[O:14]
Reactant: CCN(CC)CC
Reactant: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)c(C)c1Cl
Reaction time: 15 h

Procedure:
A suspension of 2.55 g (37.8 mM) of methanamine hydrochloride is prepared in 120 ml of dichloromethane (DCM) and 7.5 g of 2,4-dichloro-3-methylbenzenesulphonyl chloride in solution in 30 ml of DCM, and 10.5 ml of triethylamine, are added; the reaction mixture is kept under agitation for 15 hours at ambient temperature and then washed with a solution of 1N hydrochloric acid, with a solution of sodium bicarbonate, and then with water. The organic phase is dried over magnesium sulphate and then concentrated under reduced pressure. The solid residue obtained is purified by chromatography on silica gel in eluting with the aid of a mixture of cyclohexane/ethyl acetate (8/2, v/v). 6.2 g of the expected compound are thus obtained as a white solid (yield=85%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[F:1][C:2]1[C:7]([CH2:8][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(Cc1c(F)c(F)c(F)c(F)c1F)C(=O)OCC
Yield: 67.2 %

Procedure:
9 g of pentafluorobenzaldehyde are condensed on 7 g of diethyl malonate in accordance with the process described in Organic Synthesis vol. III, page 377. 10 g (69%) of diethyl pentafluorobenzylmalonate are obtained which is hydrogenated at ordinary pressure in the presence of palladium on charcoal into diethyl pentafluorobenzylmalonate (92%).
Reaction SMILES: [OH:1][C:2]([CH3:55])([CH3:54])[C@@H:3]([NH:10][C:11]([NH:13][C:14]1[CH:23]=[C:22]2[N:24](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:20]3[C:21]2=[C:16]([CH2:17][CH2:18][N:19]3CC2C=CC(OC)=CC=2)[N:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[OH:1][C:2]([CH3:55])([CH3:54])[C@@H:3]([NH:10][C:11]([NH:13][C:14]1[CH:23]=[C:22]2[NH:24][N:25]=[C:20]3[C:21]2=[C:16]([CH2:17][CH2:18][NH:19]3)[N:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CN2CCc3nc(NC(=O)N[C@@H](c4ccccc4)C(C)(C)O)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)[C@@H](NC(=O)Nc1cc2[nH]nc3c2c(n1)CCN3)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea (38 mg, 0.052 mmol) was taken in TFA (0.17 mL) and stirred at room temperature for 30 minutes. To the reaction was added triethylsilane (34 uL, 0.209 mmol) stirred for 15 minutes at room temperature then heated to 80° C. for 30 minutes. The reaction mixture was concentrated, taken in DCM and washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (S)-1-(2-hydroxy-2-methyl-1-phenylpropyl)-3-(1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)urea. MS ESI calc'd. for C19H22N6O2 [M+H]+ 367. found 367. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 9.25 (br, 2H), 7.28 (m, 4H), 7.20 (m, 1H), 6.90 (s, 1H), 4.59 (d, J=14 Hz, 1H), 3.42 (dd, J=8.0, 5.0 Hz, 2H), 2.92 (dd, J=8.0, 5.0 Hz, 2H), 1.95 (s, 3H), 1.0 (s, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([C:18]2[C:19](=[O:32])[N:20]([CH2:29][CH2:30][CH3:31])[C:21](=[O:28])[N:22]3[CH2:27][CH:26]=[CH:25][S:24][C:23]=23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[S:24]1[CH2:25][CH:26]=[CH:27][N:22]2[C:21](=[O:28])[N:20]([CH2:29][CH2:30][CH3:31])[C:19](=[O:32])[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:23]12
Reactant: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CC=CS2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)C=CCS2=O
Yield: 84.2 %

Procedure:
m-Chloroperbenzoic acid (0.34 g)was added to a solution of 9-phenyl-7-propyl-4H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (0.53 g) in methylene chloride (10 mll) little by little with stirring under ice cooling, and then, the reaction mixture was stirred at room temperature for 10 hours. An insoluble material was removed by filtration, and the filtrate was washed with a saturated aqueous sodium bicarbonate. After drying, the organic solution was concentrated to dryness. The resulting residue was purified column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless needles (0.47 g, 87%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (405 mg, 0.001 mol) in tetrahydrofuran-water (3:1) was added lithium hydroxide (128 mg, 0.003 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (0.3 g, 77%) as a yellow solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9]([OH:11])=O)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1ccccc1
Yield: 43.9 %

Procedure:
Proceeding as in Example 1, but substituting 2-phenylacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 31, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-phenylacetyl)pyrrolidine-2-carboxamide (13.4 mg, 43.9%). 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.54 (t, 2H), 7.19 (m, 12H), 6.97 (m, 4H), 3.74 (m, 1H), 3.65 (s, 2H), 3.27 (m, 2H), 2.62 (m, 4H). MS (EI) for C32H29FN2O3: 509.6 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][Cl:27])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCCl
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Yield: 52.3 %

Procedure:
A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 g, 107 mmol), 6-chloro-1-hexyne (18.71 g, 160 mmol), triethylamine (22.37 mL, 160 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.63 g, 8.02 mmol) and copper(I) iodide (3.04 g, 15.94 mmol) in N,N-Dimethylformamide (1000 mL) under nitrogen was heated to 70° C. for 4 hours. The cooled solution was evaporated and the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes. Appropriate fractions were evaporated to give the title compound as a yellow foam (25.5 g).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([CH3:32])([CH2:11][C:12](=[O:31])[NH:13][C:14]1[CH:15]=[N:16][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:19]=1)[CH2:7][C:8]([OH:10])=O.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH2:37]>ClCCl>[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36][NH:37][C:8]([CH2:7][C:6]([CH3:32])([CH3:5])[CH2:11][C:12]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])[N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:16][CH:15]=1)=[O:31])=[O:10]
Reactant: CN(C)CCN
Reactant: CN(C(=O)Oc1ccc(NC(=O)CC(C)(C)CC(=O)O)cn1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)CCNC(=O)CC(C)(C)CC(=O)Nc1ccc(OC(=O)N(C)c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 39 %

Procedure:
Thionylchloride (237 microL, 3.27 mmol) was added to a stirred solution of 3,3-dimethyl-4-[6-(methyl-phenyl-carbamoyloxy)-pyridin-3-ylcarbamoyl]-butyric acid (0.63 g, 1.63 mmol) in dichloromethane (10 mL). After stirring for 10 minutes the solution was divided into 4 equal portions of acid chloride. To one portion was added N,N-dimethylethylenediamine (0.5 mL) and after stirring for 2 hours at room temperature the crude product was purified by flash column chromatography (SiO2), yielding the title compound (74 mg, 39% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CO)cc3)nc2)CC1
Yield: 77.3 %

Procedure:
1-Methylethyl 4-[({6-[4-(hydroxymethyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (208 mg, 77%) was prepared as a white solid from 4-(hydroxy methyl)phenylboronic acid (130 mg, 0.84 mmol), 1-methylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 81, Step 1, 250 mg, 0.70 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (4 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.37 (bs, 1H), 7.94 (d, 2H, J=7.9 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.46 (d, 2H, J=8.1 Hz), 7.45-7.30 (bs, 1H), 4.91 (septet, 1H, J=6.2 Hz), 4.74 (s, 2H), 4.21 (bs, 2H), 3.90 (d, 2H, J=6.2 Hz), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 385 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([S:39][CH3:40])[N:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[C:36]([C:37]#[N:38])=[CH:35][N:34]=[C:33]([S:39][CH3:40])[N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(C)cnc32)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CSc1ncc(C#N)c(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(C)cc23)n1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
A mixture of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (306 mg, 0.74 mmol) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (207 mg, 1.12 mmol) in dioxane (9 mL) was degassed and stirred under nitrogen for 10 minutes. The reaction mixture was treated with potassium carbonate (336 mg, 2.23 mmol) and bis(tri-t-butylphosphine)palladium(0) (38 mg, 0.074 mmol) and degassed again. The reaction mixture and stirred under nitrogen for 10 minutes. Water (1.35 mL) was added and the reaction mixture was degassed and stirred under nitrogen for 2 hours. A suspension was observed. The resulting mixture was filtered and the solid was washed with dioxane and water. The solid was dried in a vacuum oven to afford the title compound as a white solid (282 mg, 87% yield).