Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([OH:15])[C:10](=[CH:13][CH:14]=2)[CH:11]=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:15][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:14]=[CH:13][C:10]=1[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: [Li]c1ccccc1
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Product: O=C(c1ccccc1)c1ccc(N2CCOCC2)cc1O

Procedure:
Following the procedure for preparing Example 34, 4-(4-morpholinyl)-salicylaldehyde (1.0 g, 5 mmol) and phenyllithium (1.8 M solution in tetrahydrofuran, 6.0 mL, 11 mmol) were converted to the product (387 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:13][O:12][C:10]([CH2:9][NH:8][C:5]1[N:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:3][CH:4]=1)=[O:11]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNc1ccc(/C=C/C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
A solution of 5-bromo-2-(methoxycarbonylmethyl)aminopyridine (4.69 g, 19.1 mmole, from Preparation 28 (c)), tert-butyl acrylate (11.2 mL, 76.5 mmole), DIEA (6.7 mL, 38.5 mmole), Pd(OAc)2 (215 mg, 1 mmole), and P(o-tol)3 (583 mg, 2 mmole) in propionitrile (100 mL) was purged with Ar, then was heated at reflux. After 18 h, the reaction was allowed to cool to room temperature then was concentrated to dryness. The residue was purified by flash chromatography on silica gel (40% EtOAc/hexane) to give the title compound (5.21 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1 H), 7.62 (dd, 1 H), 7.47 (d, J=16.0 Hz, 1 H), 6.48 (d, J=8.7 Hz, 1 H), 6.17 (d, J=15.9 Hz, 1 H), 5.21 (br s, 1 H), 4.20 (d, J=5.4 Hz, 2 H), 3.79 (s, 3 H), 1.52 (s, 1 H).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:18]3[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=3)[C:12]#[N:13])=[CH:3][N:4]=2)[N:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Clc1ccc2ncc(Br)n2n1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(-c2cnc3ccc(Cl)nn23)c1
Temperature: 110 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (2 g, 8.6 mmol) and 3-(cyano)phenylboronic acid (1.26 g, 8.6 mmol) in dioxane/H2O (100 mL, 4:1) was added K2CO3 (2.38 g, 17.2 mmol) and Pd(PPh3)4 (0.19 g, 0.172 mmol), the mixture was stirred at 110° C. for 3 h. The solution was concentrated and partitioned in EtOAc/H2O. The aqueous layer was washed with EtOAc (50 mL) 3 times. The collected organic layers were dried over Na2SO4, concentrated and purified by column chromatography to give compound 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (1.2 g, 4.71 mmol, yield 55%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1Br.[CH:13]([B-](F)(F)F)=[CH2:14].[K+]>CCO.CCOC(C)=O>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:13]=[CH2:14]
Reactant: C=C[B-](F)(F)F
Reactant: O=C1OCc2c1ccc(Br)c2Br
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1Br)COC2=O

Procedure:
4,5-Dibromo-2-benzofuran-1(3H)-one (3.00 g, 10.3 mmol), potassium vinyltrifluoroborate (12.7 g, 20.6 mmol) and Pd (dppf)Cl2 (839 mg, 1.03 mmol) in TEA (2.7 mL) and EtOH (15 mL) were heated at 60° C. for 2 h. Analysis by TLC showed clean and complete reaction. The reaction mixture was diluted with EtOAc (500 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was subjected to purification over silica gel to give 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].[NH2:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.061 mL of pyridine and 0.086 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenethylbenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature and a saturated sodium hydrogen carbonate aqueous solution was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid, aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-phenethylbenzoate.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH2:23])=[NH:22])=[CH:16][CH:15]=1)#[N:13].[Na]>C(O)C>[OH:9][C:1]1[CH:2]=[C:3]([OH:5])[N:23]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[N:22]=1
Reactant: N#Cc1ccc(NC(=N)N)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: N#Cc1ccc(Nc2nc(O)cc(O)n2)cc1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Diethyl malonate (30 gm) was added to 1-(4-cyanophenyl)guanidine (30 gm) at room temperature. A solution of sodium (17.2 gm) in ethanol (450 ml) was added to the above reaction mass. The contents were heated to reflux and maintained for 12 hours. Distilled off the solvent completely under vacuum and then added water (500 ml). The reaction mass was stirred for 30 minutes and filtered. The solid obtained was dried to obtain 40 gm of 4-(4,6-dihydroxypyrimidine-2-yl-amino)benzonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:13]1[CH:18]=[C:17](C=O)[C:16]([CH:21]=O)=[CH:15][CH:14]=1>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:21][C:16]3[C:15](=[CH:14][CH:13]=[CH:18][CH:17]=3)[C:11]2=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccccc1C=O
Reactant: CC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Yield: 42.6 %

Procedure:
A mixture of 4-acetylphenylisocyanate (27.5 g, 0.17 mol) and o-phthalicdicarboxaldehyde (25.0 g, 0.186 mol) is heated in an oil bath at 170°-175° C. for 4.0 hours under nitrogen atmosphere. On cooling the melt solidified which is pulverized and refluxed with CH2Cl2 and CH30H and filtered to give 18.2 g (41.4%) of the desired 2-(4-acetylphenyl)-2,3-dihydro-lH-isoindole-1-one, mp 235°-237° C. The residue is recrystallized from DMF (1800 ml). Yield 13.0 g (29.6%), mp 236°-239° C. (Jap. patent J5 7050-960; mp 243°-244° C. for the nonsolvated compound, prepared by a different route).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCCCCBr
Product: O=C(Cl)CCCCCCCBr
Reaction time: 2 h

Procedure:
8-Bromooctanoic acid (2.0 g, 8.97 mmol, commercially available e.g. from Aldrich) in thionyl chloride (2 ml) was stirred at room temperature for 1 hour and then at 100° C. for 2 hours. The thionyl chloride was removed by evaporation and the residue was co-evaporated with dichloromethane (2×30 ml) to give 8-bromooctanoyl chloride as a colourless mobile oil (2.05 g).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:2].C[Li].[CH2:14](OCC)C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[CH:1]([OH:2])[CH3:14])[CH:8]=[CH:9]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CCOCC
Agent: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cccc2cc[nH]c12
Yield: 94.5 %

Procedure:
Add 7-formylindole (1.0 g, 6.89 mmol) in anhydrous tetrahydrofuran (15 ml) dropwise to a solution of 1.4M methyllithium in diethyl ether (12.2 ml, 17.1 mmol) at −78° C. After 15 minutes add saturated aqueous sodium bicarbonate (15 ml). Dilute with 1:1 ethyl acetate: diethyl ether, wash with saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide desired compound (1.05 g, 94%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1.[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[Cl:14][C:15]1[C:16]([CH3:25])=[C:17]([S:21]([NH:13][C:10]2[S:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:9]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccccc2Cl)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(2-chlorophenyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (45.3 mg) with purity >90%: MS (pos) m/z 399.1, 401.1; HRMS m/z 397.9711 (calc. of monoisotopic mass for C16H12Cl2N2O2S2 gives 397.9117).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CC(O)=O>[Cl:12][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccnc2ccccc12
Solvent: CC(=O)O
Product: O=c1c(Cl)c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxyquinoline (5.33 g, 36.7 mmol) in AcOH (184 mL) was treated with N-chlorosuccinimide (6.37 g, 47.7 mmol) and the yellow homogeneous mixture was stirred and heated at 60° C. After 3 h, the mixture was cooled to room temperature and concentrated in vacuo. Saturated aqueous NaHCO3 solution (300 mL) was added until pH became ˜8.5. The resulting solid was collected by filtration, washed with water (300 mL), and dried under high vacuum to give 3-chloroquinolin-4(1H)-one (A275-1) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.28 (1H, br. s.), 8.40 (1H, d, J=6.5 Hz), 8.15 (1H, dd, J=8.2, 1.4 Hz), 7.65-7.73 (1H, m), 7.58-7.63 (1H, m), 7.39 (1H, ddd, J=8.1, 6.9, 1.2 Hz); LCMS (ESI) m/z 180.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: COc1cc(CN)cc(OC)c1OC
Solvent: CCN(CC)CC
Product: COc1cc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1OC

Procedure:
2-Chloro-6-(3,4,5-trimethoxybenzylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,4,5-trimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([S:30][CH3:31])=[N:28][N:29]=2)[N:26]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([S:30][CH3:31])=[N:28][N:29]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nnc2ccc(Cl)nn12
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: CSc1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 6-chloro-3-methylsulfanyl-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-(4-benzhydrylpiperazin-1-yl)-3-methylsulfanyl-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1>>[F:25][C:22]1[CH:23]=[C:24]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:19]=[CH:20][C:21]=1[F:26]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Fc1ccc(Br)cc1F
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(F)c(F)c1)O2

Procedure:
Reaction of rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 1-bromo-3,4-difluorobenzene under the conditions described in Example 26 and extending the reaction time to 42 hours gave after chromatographic isolation (40 fold amount of silica gel using methylene chloride) and crystallization from petroleum ether colorless crystals of the title compound with m.p. 109°-112°.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21][CH2:22]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:22][CH2:21][CH2:20][C:19]#[C:18][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: C1CNC1
Product: FC(F)(F)c1ccc(-c2nsc3cc(C#CCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 17.1, Methanesulfonic acid 5-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and azetidine were converted to yield 6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole as orange oil, MS: 401 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:23])[F:24])=[O:16])[CH2:5][NH2:6]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-trifluoromethyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (0.19 g, 0.34 mmol) in DCM (6 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature 1 h and evaporated. Isolate 0.23 g of crude product which was used without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:32][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=O)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:32][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH2:27][N:29]([CH3:30])[CH3:31])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)Cc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCc1cnc2[nH]c(C(CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N,N-dimethyl-acetamide (as prepared in Example 39, 30 mg, 0.066 mmol) and lithium aluminum hydride (5 mg, 0.13 mmol) in dry tetrahydrofuran (3 mL) was refluxed for 4 h. The mixture was then cooled to room temperature, quenched with a 15% aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded (2-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-ethyl)-dimethyl-amine (15 mg, 50%) as a colorless oil: LC/MS m/e calcd for C25H33N3O2S [M+H]+ 440.62, observed 440.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (m, 2H), 1.49 (m, 2H), 1.64 (m, 2H), 1.67-1.86 (m, 3H), 2.09 (m, 1H), 2.26 (m, 1H), 2.56 (br. s., 6H), 2.81 (s, 2H), 3.03 (s, 2H), 3.05 (s, 3H), 4.27 (t, J=7.8 Hz, 1H), 6.33 (s, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 7.84 (br. s., 1H), 7.90 (d, J=8.3 Hz, 2H), 10.38 (br. s., 1H).
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>CO.[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (2S,3S,5S)-2-(N,N-dibenzylamino)-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (12 g, 21.3 mmol) in methanol (350 mL) was charged ammonium formate (8.05 g, 128 mmol, 6.0 eq) and 10% palladium on carbon (2.4 g). The solution was stirred under nitrogen at 60° C. for three hours and then at 75° C. for 12 hours. An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacial acetic acid. The reaction was driven to completion within 2 hours at a reflux temperature. The reaction mixture was then cooled to room temperature and then filtered through a bed of celite. The filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure. The residue was taken up in 1N NaOH (300 mL) and extracted into methylene chloride (2×200 mL). The combined organic layers were washed with brine (250 mL) and dried over sodium sulfate. Concentration of the solution under reduced pressure provided the desired product as a light colored oil which slowly crystallized upon standing (5 g). Further purification of the product could be accomplished by flash chromatography (silica gel, 5% methanol in methylene chloride). 300 MHz 1H NMR (CDCl3) δ1.42 (s, 9H), 1.58 (m, 1H), 1.70 (m, 1H), 2.20 (s, broad, 2H), 2.52 (m, 1H), 2.76-2.95 (m, 4H), 3.50 (m, 1H), 3.95 (m, 1H), 4.80 (d, broad, 1H), 7.15-7.30 (m, 10H).
Reaction SMILES: [CH:1]1([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([OH:22])(=[O:21])[CH3:20].Cl>O>[CH:1]1([C:7]2[CH:14]=[CH:13][C:20]([C:19]([OH:22])=[O:21])=[CH:9][C:8]=2[C:15]([F:16])([F:17])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
A mixture of 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (Preparation 118A, 8 g, 31.6 mmol), acetic acid (30 mL), conc. hydrochloric acid, 37% (30 mL) and water (60 mL) was stirred at 110° C. under nitrogen (oil bath temp.) for 20 h. After water (100 mL) was added, the mixture was cooled. The solid was filtered, washed with water (3×15 mL) and dried to give 4-cyclohexyl-3-(trifluoromethyl)benzoic acid (7 g, 25.7 mmol, 81% yield) as a brownish solid. The compound had an HPLC retention time=3.80 min. (condition C); LC/MS M+1=273.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([NH:11]CC2OC(C3C=C4C(=CC=3)C(=NO)CC4)=C(C3C=CN=CC=3)C=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][CH:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: COCCN1CCC(NCc2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A solution of the product from Step 1 (500 mg, 1.94 mmol) in dichloromethane (5 ml) was cooled to 0° C. and treated with trifluoroacetic acid (2 ml). The mixture was allowed to warm to room temperature and stirred for a further 1 hour. After evaporation of the solvent in vacuo, the residue was partitioned between dichloromethane and an aqueous solution of sodium carbonate. After separation of the layers the aqueous phase was re-extracted six times with dichloromethane, dried and concentrated in vacuo to yield the title compound (145 mg, 47%); 1H NMR (CD3OD) 3.49 (2H, t, J 5.2 Hz), 3.35 (3H, s), 3.30 (2H, m), 3.10 (1H, s), 2.80 (2H, t, J 5.2 Hz), 2.68 (2H, m), 1.91 (2H, m), 1.30 (2H, m).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([F:10])=[CH:4][CH:3]=1>CO>[F:10][C:5]1[C:6]([CH2:8][OH:9])=[N:7][CH:2]=[CH:3][CH:4]=1
Reactant: OCc1nc(Br)ccc1F
Solvent: CO
Product: OCc1ncccc1F
Reaction time: 20 h

Procedure:
Dissolve (6-bromo-3-fluoro-pyridin-2-yl)-methanol (850 mg, 4.13 mmol) in methanol (40 mL) then purge the solution with nitrogen. Add palladium on carbon (200 mg of 5% wet) and stir the mixture under a hydrogen atmosphere (2 balloons) for 20 h. Filter the mixture through Celite® and wash the filter cake with methanol.