Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].C(#[N:17])C.[ClH:18].C(O)C>>[ClH:18].[NH2:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CC#N
Agent: Cl
Solvent: CCO
Product: NCC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (22 g), NaN(CHO)2 (9.5 g) and acetonitrile (50 mL) was stirred at room temperature for 3 hr and at 70° C. overnight, and the insoluble material was removed by filtration. The filtrate was concentrated to give an oil. The oil was dissolved in hydrogen chloride-ethanol, and the mixture was stirred at room temperature for 48 hr. The resulting precipitate was collected by filtration, and washed with ether to give the title compound (2.7 g) as a solid. The filtrate was concentrated, and the residue was dissolved in water. The aqueous layer was washed with ether, and the solvent was evaporated under reduced pressure to give the title compound (7.0 g).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:19][CH2:20][CH3:21])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])(OCC)=O.C=O>>[CH3:1][C:6]1[NH:7][C:8]([CH2:19][CH2:20][CH3:21])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCc1[nH]c(C(=O)OCC)c(CCC(=O)OCC)c1C
Agent: C=O
Product: CCCc1[nH]c(C)c(CCC(=O)O)c1C

Procedure:
2-Carbethoxy-3-carbethoxyethyl-4-methyl-5-n-propyl-pyrrole was reductively alkylated with paraformaldehyde to yield 2,4-dimethyl-3-carboxyethyl-5-n-propyl-pyrrole. ##STR116##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1noc(CN)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1noc(CNC(=O)c2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (CAN 1018782-82-5) and 3-methyl-1,2,4-oxadiazole-5-methanamine (CAN 90928-92-0) as starting materials; LC-MS (UV peak area/ESI) 100%, 425.0644 (M−H)−.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[NH:28][C:22]3[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=3[CH:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CC([O-])(C)C.[K+].[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([NH2:44])=[O:43])=[N:40][CH:41]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]=[C:16]([C:19]2[NH:28][C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:35][C:36]4[CH:41]=[N:40][C:39]([C:42](=[O:43])[NH2:44])=[CH:38][CH:37]=4)[C:21]=3[CH:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: NC(=O)c1ccc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4ccc(C(N)=O)nc4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into the DMF (1 mL) solution of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (122 mg, 0.363 mmol) was added t-BuOK (1M in t-BuOH, 0.726 mL, 0.726 mmol) dropwise at RT under N2 over 5 min. The mixture was then put in an ice/water bath and stirred for 10 min. After that time, the DMF (1 mL) solution of 5-aminopyridine-2-carboxylic acid amide (99.5 mg, 0.726 mmol) was added into the above mixture dropwise. The reaction mixture was warmed to RT. Pd2(dba)3.CHCl3 (9.4 mg, 2.5% eq.) and R(+)-BINAP (22.6 mg, 0.1 eq.) were added, and the mixture was heated at 100° C. for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The crude was submitted to MS directed purification. A brown oil was obtained that was purified further by HPLC to obtain the title compound as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ=1.50 (s, 9H), 2.50 (m, 2H), 3.64 (t, 2H, J=5.6 Hz), 4.12 (brs, 2H), 6.50 (brs, 1H), 6.88 (s, 1H), 7.53 (d, 1H, J=4.2 Hz), 8.04-8.05 (m, 1H), 8.08 (d, 1H, J=8.8 Hz), 8.44 (s, 1H), 8.68 (dd, 1H, J=2.4 & 8.4 Hz), 9.12 (d, 1H, J=2.4 Hz), 9.91 (s, 1H), 12.18 (s, 1H). MS (ES+): m/z 436.10 (100) [MH+]. HPLC: tR=2.75 min (ZQ2000, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].[Cl-].[Na+]>C1(C)C=CC=CC=1.NCCC1C=CC=CC=1[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.COC(C)(C)C>[N:17]1([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: C1COCCN1
Agent: NCCc1ccccc1[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
1.5 g (4.6 mmol) of the compound of Example 15A and 0.48 g (5.5 mmol) of morpholine were dissolved in 15 ml of toluene, and the mixture was degassed with argon. 75 mg (0.09 mmol) of [2-(2-aminoethyl)phenyl](chloro)palladium-dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane/tert-butyl methyl ether adduct, 44 mg (0.09 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane and 1.06 g (11.0 mmol) of sodium tert-butoxide were added successively to this solution. The reaction was stirred in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 130° C. for 30 min. The reaction was then stirred into 10 ml of saturated aqueous sodium chloride solution and extracted twice with in each case 30 ml of ethyl acetate. The organic phase was washed with pH 4 buffer solution, dried over sodium sulphate and concentrated on a rotary evaporator. The residue was dissolved in 5 ml of tert-butyl methyl ether, and 10 ml of pentane were added. The precipitate formed was filtered off and dried. This gave 1.04 g (68% of theory) of the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1.Cl.[SH2:27]>CN1CCCC1=O.O>[SH:27][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: S
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C(=O)c1ccc(S)cc1)N1CCOCC1

Procedure:
451 g of hydrated sodium sulfide (Na2S content 32-38%≈2 mols) are suspended in 800 ml of N-methyl-2-pyrrolidone and 400 ml of toluene and the mixture is warmed to 130°. Approx. 290 ml of water are removed in a water separator, and the toluene is then removed by distillation. 100 g (0.37 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholinopropan-1-one are introduced into the warm solution in portions, and the suspension is heated at 140° for 12 hours. After cooling, the pH of the reaction mixture is adjusted to 6 by adding 6N HCl, and the solution is freed from H2S. The solution is then diluted with 1 liter of water and extracted with diethyl ether. The ether extracts are extracted by shaking several times with 20% sodium hydroxide solution, and the combined aqueous alkaline extracts are neutralised with 6N HCl and extracted by shaking with diethyl ether. The ether extracts are dried over MgSO4 and concentrated. The oil which remains is crystallised from cyclohexane. Melting point 68°-69° C. (Compound No. 22).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)=[O:5]
Reactant: ClCC1CO1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1

Procedure:
A solution of 3.5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide and 1.9 g of potassium carbonate in 100 ml of acetone was refluxed for 30 hours under an inert atmosphere with 11 ml of epichlorohydrin and the insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was purified by chromatography over silica (eluent: chloroform/acetone/TEA 6:3:1). Fractions having a Rf=0.45 were evaporated to dryness and the residue was empasted with ether, filtered and dried under reduced pressure at 60° C. to obtain 3.65 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)benzamide melting at 171° C.
Reaction SMILES: N1C=CC(CC2N=C(N)OC=2)=CC=1.Cl[C:15]1[O:16][C:17]([C:20]2[CH:21]=[C:22]([CH:25]=[C:26]([NH:28][C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH:27]=2)[C:23]#[N:24])=[CH:18][N:19]=1.[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41]>CC(O)C>[CH3:36][O:37][CH2:38][CH2:39][N:40]([CH3:41])[C:15]1[O:16][C:17]([C:20]2[CH:21]=[C:22]([CH:25]=[C:26]([NH:28][C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=3)[CH:27]=2)[C:23]#[N:24])=[CH:18][N:19]=1
Reactant: Cc1ccnc(Nc2cc(C#N)cc(-c3cnc(Cl)o3)c2)c1
Reactant: CNCCOC
Agent: Nc1nc(Cc2ccncc2)co1
Solvent: CC(C)O
Product: COCCN(C)c1ncc(-c2cc(C#N)cc(Nc3cc(C)ccn3)c2)o1

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-*(pyridin-4-ylmethyl)-oxazol-2-amine above from 3-(2-chloro-oxazol-5-yl)-5-(4-methyl-pyridin-2-ylamino)-benzonitrile and N-(2-methoxyethyl)methylamine in iPrOH. (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.18 (d, J=1.7 Hz, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.87 (t, J=1.7 Hz, 1H), 7.49 (t, J=1.4 Hz, 1H), 7.41 (s, 1H), 6.70 (d, J=5.3 Hz, 1H), 6.68 (s, 1H), 3.64-3.60 (m, 2H), 3.60-3.55 (m, 2H), 3.29 (s, 3H), 3.11 (s, 3H), 2.26 (s, 3H) (ESI+) m/z 364 (M+H)+. Retention time=2.55 mins (method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)cc1
Yield: 80 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 80%). 1H NMR (200 MHz, CDCl3): δ 2.48 (s, 3H), 3.16-3.14 (m, 4H), 3.78-3.82 (m, 6H), 4.13 (s, 4H), 6.84-7.02 (m, 4H), 7.14-7.33 (m, 3H), 7.53-7.64 (m, 1H).
Reaction SMILES: O[C:2]1([CH2:13][C:14]2[C:15]([C:20]([NH:22][CH3:23])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH3:12]>S(=O)(=O)(O)O>[CH3:12][N:3]1[C:2]2([CH2:13][C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20](=[O:21])[N:22]2[CH3:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: CNC(=O)c1ccccc1CC1(O)c2ccccc2C(=O)N1C
Agent: O=S(=O)(O)O
Product: CN1C(=O)c2ccccc2CC12c1ccccc1C(=O)N2C

Procedure:
A mixture of 9.1 grams (0.0294 mole) of α-(1-hydroxy-2-methyl-3-oxoisoindolin-1-yl)-N-methyl-o-toluamide and 180 milliliters of 2 M sulfuric acid is refluxed for 20 hours. The mixture is cooled and the solid separated by filtration. The solid is then dissolved in methylene chloride and washed twice with water and once with brine. The organic phase is dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is crystallized from ethanol to give 2,2'-dimethyl spiro[isoindolin-1,3'(4'H)-isoquinoline]1',3-dione, m.p. 202° - 203° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:22][C:21](=[O:23])[C:20]4[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=4[O:24][CH3:25])[N:14]=3)=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35](=[O:37])[CH3:36])[CH2:3]3)=[CH:8][CH:9]=1)=[N:14]2
Reactant: CC(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)C4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NC(C)=O)C4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of 2-(4-(3-aminopyrrolidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.150 g, 0.41 mmol) in CH2Cl2 (10 mL) was treated with Et3N (0.114 mL, 0.82 mmol), cooled to 0° C., and acetyl chloride (0.029 mL, 0.41 mmol) was added. The mixture was stirred for 2 hours at room temperature, concentrated, and purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. The mixture was further purified by flash chromatography on silica gel, eluting with 9:1 methylene chloride/methanol, to afford the title compound (0.130 g, 78%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 11.67 (s, 1H), 8.18 (d, J=6.8 Hz, 1H), 8.14 (d, J=6.8 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.60 (d, J=9.0 Hz, 2H), 6.44 (d, J=2.3 Hz, 1H), 4.36-4.39 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.13-3.59 (m, 5H), 2.15-2.22 (m, 1H), 1.90-1.94 (m, 1H), 1.82 (s, 3H). ESI MS m/z 409 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH3:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:17])=[C:10]([S:13]([NH2:18])(=[O:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N1CCc2cc(Br)c(S(=O)(=O)Cl)cc21
Product: CC(=O)N1CCc2cc(Br)c(S(N)(=O)=O)cc21
Yield: 64.6 %

Procedure:
A solution of 1-acetyl-5-bromoindoline-6-sulfonyl chloride (2.30 g, 6.79 mmol) in NH3 (54.3 mL, 27.2 mmol, 0.5M solution in dioxane) was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was triturated with CH2Cl2 to give the title compound (1.40 g, 65%) as a brown solid. 1H NMR (DMSO-d6) δ 8.73 (s, 1H), 7.63 (s, 1H), 7.15 (s, 2H), 4.15 (t, J=8.5 Hz, 2H), 3.19 (t, J=8.6 Hz, 2H), 2.17 (s, 3H); MS(ESI+) m/z 321.1 (M+H)+.
Reaction SMILES: C1(CC[CH2:9][CH2:10][P:11]([OH:13])[OH:12])C=CC=CC=1.C([CH:21](Br)[C:22]([O-:24])=[O:23])C1C=CC=CC=1>>[OH:13][P:11]([CH2:21][C:22]([OH:24])=[O:23])([CH2:10][CH3:9])=[O:12]
Reactant: OP(O)CCCCc1ccccc1
Reactant: O=C([O-])C(Br)Cc1ccccc1
Product: CCP(=O)(O)CC(=O)O

Procedure:
Following the procedure as set out in Example 1, except substituting ethylphosphonous acid for 4-phenylbutylphosphonous acid, and substituting chloroacetic acid for benzylbromoacetate, the title compound is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:11]=1[CH2:18][N:19]([CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[NH2:17][CH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][N:19]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:28][C:29]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][N:30]=2)=[C:10]([CH2:9][OH:8])[CH:15]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccnc1CN(Cc1ccc(CN)cc1CO)Cc1ncccc1C
Yield: 27 %

Procedure:
To a cold (0° C.) mixture of LiAlH4 (195 mg, 5.12 mmol) in dry THF (6 mL) was added 2-{[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.22 g, 0.55 mmol) as a solution in THF (5 mL). The resultant mixture was stirred at room temperature for 5 hours then cooled in an ice water bath. The mixture was treated with saturated aqueous sodium-potassium tartrate (11 mL) and diluted with THF (11 mL). The phases were separated and the aqueous phase was extracted with THF (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) gave COMPOUND 385 (56 mg, 26%) as a white solid. 1H NMR (CDCl3) δ 2.12 (s, 6H), 3.72 (s, 4H), 3.82 (s, 2H), 3.89 (s, 2H), 4.25 (s, 2H), 6.54 (br s, 1H), 7.05 (dd, 2H, J=4.8, 7.5 Hz), 7.14-7.17 (m, 1H), 7.22-7.28 (m, 2H). 7.37 (d, 2H, J=7.2 Hz), 8.36 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.57, 46.53, 57.74, 59.20, 63.53, 122.76, 126.35, 130.26, 132.06, 133.38, 135.74, 138.46, 142.44, 143.79, 146.51, 156.35; ES-MS m/z 377 (M+H). Anal. Calcd. for C23H28N4O.0.2H2O: C, 72.68; H, 7.53; N, 14.74. Found: C, 72.69; H, 7.52; N, 14.40.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:5]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].[NH:26]1[CH:30]=[N:29][N:28]=[N:27]1>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH:6]2[N:5]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH:4]([CH2:3][CH2:2][N:27]3[N:28]=[N:29][CH:30]=[N:26]3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCn3ncnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=416.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(2-chloro-ethyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4].[CH3:39][NH:40][CH3:41]>C1COCC1>[CH3:39][N:40]([CH3:41])[CH2:2][C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=2)[CH:13]=[C:14]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])=[O:18])[N:15]=1)=[O:10])=[O:4]
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCOC(=O)CCl)n1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCOC(=O)CN(C)C)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
114.5 mg (0.2 mmol) of 2-[({4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazol-2-yl}carbonyl)amino]ethyl chloroacetate (Example 26A) are dissolved in 2 ml of a 2 molar solution of dimethylamine in THF. The reaction mixture is shaken in a tightly closed reaction vessel at RT for 16 h and then left to stand at RT for 64 h. The reaction solution is then evaporated, and the residue from the evaporation is dissolved in DMF, filtered and purified by preparative HPLC (Method 9).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:16])[N:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C[C:47]([N:49](C)C)=O>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn].[C-]#N.[Zn+2].[C-]#N>[C:47]([C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([CH3:16])[N:3]=1)#[N:49]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(C1C=Cc2ccccc2C1c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(C#N)n1
Temperature: 95 °C

Procedure:
tert-butyl (2-chloro-6-methylpyridin-4-yl)carbamate (220 mg, 0.91 mmol) from Step 2 of this example, palladium (II) trifluoroacetate (13 mg, 0.039 mmol), zinc dust (11.3 mg, 0.17 mmol), me-2-(di-t-butylphosphino)-1H-binaphthyl (32 mg, 0.08 mmol), zinc cyanide (59.6 mg, 0.51 mmol) was added dimethylacetamide (4.8 mL) in a flask (flame-dried) and evacuated and back-filled with N2 (3×). The reaction was heated to 95° C. for 30 min, cooled to room temperature. Water (50 mL) was added, extracted with ethyl acetate (50 mL), second wash with brine (50 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel pad (1 inch deep), concentrated and purified by column chromatography through a 40 gram RediSep Rf™ silica gel cartridge eluting with 18% ethyl acetate/hexanes to give the title compounds as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)=[O:10])=[CH:5][N:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[O:10])=[CH:5][N:4]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(OC)nc2)cc1)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)NCCOc2ccc(CC(Oc3ccccc3)C(=O)O)cc2)cn1
Yield: 83.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(2-methoxypyridine-5-carbonylamino)ethoxy]phenyl]-2-phenoxypropionate (330 mg), which is the product of Example 84, was reacted with aqueous sodium hydroxide solution (1N, 2.50 ml) and the reaction mixture was treated to give the title compound (260 mg) as colorless crystals.