Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][N:40]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCN(S(C)(=O)=O)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-4-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (D80, 100 mg, 0.16 mmol) in 5 mL of dichloromethane were added triethylamine (44 μL, 0.32 mmol, 2 eq.) and, at 0° C., methanesulfonyl chloride (18 μL, 0.24 mmol, 1.5 eq.). The reaction was left at room temperature overnight. Additional 3 eq. of methanesulfonyl chloride were added. It was then diluted with dichloromethane, extracted with sat. NaHCO3, the organics dried (Na2SO4), and the solvent was removed. The product was purified by flash chromatography (silica, EtOAc). Obtained 60 mg of the title compound.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:95])[CH3:94])=[O:89])[C@@H:85]([CH3:87])[OH:86]>CN(C=O)C>[NH2:1][C@H:2]([C:27]([NH:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:94])[CH3:95])=[O:89])[C@@H:85]([CH3:87])[OH:86])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O)C(=O)O
Reaction time: 0.03 h

Procedure:
In an RBF were mixed Fmoc-Gln(Trt)-OH (44.7 g, 73.2 mmol), BOP (40.4 g, 91.5 mmol) and 250 ml of DMF. The mixture was stirred for 2 min and then DIPEA (18.9 g, 146.4 mmol) was added. The resulting mixture was added in one portion to the pre-swollen H-Thr-Leu-Resin and the reaction mixture was stirred for 2.5 h, the Kaiser test was negative, then the reaction was considered to be complete and the reaction medium was removed via filtration.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:20]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)Nc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (82.1 g, 0.813 mole) was added to a stirred suspension of 2-chloro-3-nitropyridine (51.4 g, 0.325 mole) and (S)-alanine ethyl ester hydrochloride (75 g, 0.488 mole) in absolute ethanol (500 ml). After refluxing for 10.5 hr. and stirring at room temperature overnight, the solvents were evaporated under reduced pressure. The residue was triturated in 500 ml of ethyl acetate, filtered, and the filter cake was rinsed with ethyl acetate. The filtrate was washed three times with water, dried over sodium sulfate, filtered and evaporated to an oil weighing 85.6 g. A 1.25-g sample of the oil was eluted through 20 g of silica gel with isopropyl ether as the eluting solvent to give a pure fraction. The solvent was evaporated and the residual oil was dissolved in methylene chloride, filtered, and evaporated to an oil which was dried under high vacuum at 50° C. overnight to give 0.9 g of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>S(Cl)(Cl)=O>[NH:22]1[C:21]([NH:20][C:17]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=3)[N:5]=2)=[O:19])=[N:25][N:24]=[N:23]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(C(=O)O)nc(-c2cccc([N+](=O)[O-])c2)c1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2nnn[nH]2)nc(-c2cccc([N+](=O)[O-])c2)c1
Yield: 50.8 %

Procedure:
In the same manner as described in Example 13-(1), 4-methyl-6-(3-nitrophenyl)-2-pyridinecarboxylic acid (3.0 g), thionyl chloride (30 ml) and 5-aminotetrazole (1.2 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(3-nitrophenyl)-2-pyridinecarboxamide (1.92 g). M.P. 288°-290° C. (decomp.) (recrystallized from dimethylformamide)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 40.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (203 mg) described in Preparation Example 211 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (86 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([O:21][CH3:20])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 85.7 %

Procedure:
A solution of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.26 g, 0.81 mmol) and sodium methoxide (prepared from 75 mg of sodium, 3.26 mmol) in dry MeOH (15 mL) is heated at 90° C. in a pressure vessel for 18 h. The mixture is poured into water and extracted with EtOAc to give 4-(3-bromoanilino)-7-methoxypyrido[2,3-d]pyrimidine (0.23 g, 86%). 1H NMR (DMSO) δ 9.88 (1H, brs), 8.82 (1H, d, J=8.9 Hz), 8.71 (1H, s), 8.18 (1H, dd, J=8.0, 1,9 Hz), 7.36 (1H, dd, J=8.1, 8.0 Hz), 7.29 (1H, ddd, J=8.1, 1.9, 1,9 Hz) 7.15 (1H, d, J=8.9 Hz), 4.01 (3H, s).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[I:19]I>CN(C)C=O>[I:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Reactant: II
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(I)c2[C@@H]2CCCN12

Procedure:
44.26 g (185 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was stirred at 100° for 4 hours with 162.8 g (645 mmol) of iodine in 300 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in water and methylene chloride, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted four times with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. By chromatography of the crude product on silica gel while eluting with ethyl acetate and subsequent recrystallization from methylene chloride and methanol there was obtained (S)-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 222°-223°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].[OH-:20].[Na+:21]>O>[OH2:15].[OH2:20].[NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+:21]
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1C(=O)c1ccccc1
Yield: 70 %

Procedure:
A mixture of 2.6 g. of (2-amino-3-benzoylphenyl)acetic acid and sodium hydroxide (0.1 mole) in 25 ml. of water was stirred for approximately 10 min. and then heated to reflux under nitrogen. The reaction mixture was then cooled and filtered. The filtrate was evaporated down to approximately 2 ml., refiltered and a large volume of acetone added to the filtrate to precipitate the product as bright yellow flakes. Yield 70%.
Reaction SMILES: CO.N1CC[CH2:6][CH2:5][CH2:4]1.[ClH:9].Cl.C[O:12][C:13]([C:15]1[CH:38]=[CH:37][C:18]([CH2:19][NH:20][C:21]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[NH:25])=[NH:22])=[CH:17][CH:16]=1)=[O:14]>CC(C)=O>[ClH:9].[CH3:4][C:5]1([CH3:6])[N:22]=[C:21]([NH:20][CH2:19][C:18]2[CH:37]=[CH:38][C:15]([C:13]([OH:12])=[O:14])=[CH:16][CH:17]=2)[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N:25]1
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccc(C(=O)OC)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(C(=O)O)cc2)N1

Procedure:
50 ml of methanol, 100 ml of acetone and 1.6 ml of piperidine were added to 5.0 g (10.8 mmol) of N1-(4-methoxycarbonylbenzyl)-N5-decyl-biguanide dihydrochloride. The mixture was refluxed for 24 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform/methanol/acetic acid (8:0.7:0.7→8:1:1)). 4.0 g of the purified product was dissolved in 60 ml of ethanol, and to the solution were added 60 ml of water and 2.4 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 2 hours, and 5 ml of concentrated hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure, and extracted with chloroform. The aqueous layer was separated, and the solvent was distilled off under reduced pressure. The residue was dried well under reduced pressure, heated and extracted with methanol. The extract was filtered, and cooled. The resulting precipitates were filtered, and the solvent of the filtrate was distilled off under reduced pressure. The residue was extracted with ethanol under heating, and filtered. The solvent of the filtrate was distilled off under reduced pressure, and ether was added to the residue to obtain 3.4 g of a white yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5](Cl)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5]([NH:31][C@H:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:30])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 145 °C
Yield: 98.1 %

Procedure:
A mixture of 3,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine (Method 27, 0.25 g, 0.75 mmol), (s)-1-(4-fluoro-phenyl)-ethylamine (0.13 g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 145° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g, 98%). 1H NMR (400 MHz) δ 12.22 & 11.40 (s, 1H), 9.74 & 9.37 (s, 1H), 8.93 (d, J=7.6 Hz, 1H), 8.33 & 8.27 (s, 1H), 7.34 & 7.27 (m, 2H), 7.12 & 7.05 (m, 2H), 5.75 & 5.62 (s, 1H), 5.35 & 5.25 (m, 1H), 4.66 & 4.03 (m, 1H), 1.55 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 434. Found: [M+H]+ 435.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2.C(=O)([O-])[O-:17].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:2]([CH2:3][CH2:4][CH2:5][CH:6]=[C:7]1[CH2:14][CH2:13][CH:12]2[CH:8]1[CH2:9][C:10](=[O:15])[CH2:11]2)([OH:17])=[O:1]
Reactant: O=C1CC2CCC(CCCCCO)C2C1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)CCCC=C1CCC2CC(=O)CC12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-(5-Hydroxypent-1-yl)bicyclo[3.3.0]octan-7-one {hexahydro-4-(5-hydroxyheptyl)-2(1H)-pentalenone} (0.5 g, 2.4 mmoles) is mixed with a 10% solution of sodium carbonate (0.51 ml). The reaction is cooled in an ice bath and solution of potassium permanganate (0.48 g dissolved in 12 ml water) is slowly added over 10 minutes. The ice bath is then removed and the reaction mixture stirred at room temperature for 12 hour, after which time the precipitated manganese dioxide is filtered off and the filtrate partitioned between ether. The solution is acidified with dilute sulfuric acid and the organic layer separated. The aqueous phase is extracted with ether (2×20 ml), and the ether extracts combined and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear colorless oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under reduced pressure leaving a clear, colorless oil (0.050 g, 0.22 mmoles).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:36](=[O:38])[CH3:37])[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25](O)[C:24]=3[CH2:33][CH2:34][CH3:35])=[CH:13][CH:14]=2)[CH:9]=1.[OH-:40].[Na+]>CO>[C:36]([C:11]1[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=2[CH2:33][CH2:34][CH2:35][OH:40])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])[CH:17]=[CH:16]2)(=[O:38])[CH3:37]
Reactant: [OH-]
Reactant: CCCc1c(OCCCOc2ccc3ccc(OCCCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1ccc(OCCCOc2ccc3ccc(OCCCC(=O)O)cc3c2C(C)=O)c(CCCO)c1
Yield: 64 %

Procedure:
A mixture of 1.44 g of 4-[[8-acetyl-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester and 27 ml of 1N sodium hydroxide in 54 ml of methanol was stirred at reflux for an hour. The methanol was removed in vacuo and the clear solution was acidified to pH 3. The precipitate was extracted with chloroform and dried. The resulting semi-solid was purified by flash column chromatography (eluting with 2% methanol/ethylacetate) to yield 0.9 g (64%) of 4-[[8-Acetyl-7-[3-(4-acetyl-3-hydroxypropylphenoxy)propoxy]-2-naphthalenyl]oxy]butanoic acid of mp 121°-124°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) was concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added. The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4](N)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:15]>O>[Br:15][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:9][CH3:10]
Reactant: Br
Reactant: COc1c(N)cccc1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Hydrobromic acid (48% in water, 140 mL) is added slowly to an aliquot of 11 (14.33 g, 101.5 mmol) cooled to 0° C. The resulting solid is broken up with a glass rod and stirred vigorously at 0° C. for 10 min. A solution of sodium nitrite (7.40 g, 107.2 mmol) in water (50 mL) is added slowly (˜1.5 h) to the stirred slurry containing 3-fluoro-2-methoxyphenylamine and hydrobromic acid, maintaining the temperature of the reaction mixture below 5° C. A purple solution of cuprous bromide (9.62 g, 67.1 mmol) in hydrobromic acid (48% in water, 50 mL) is added dropwise to the reaction mixture, maintaining the temperature of the reaction mixture below 5° C. The resulting reaction mixture is heated at 60° C. until the evolution of gas ceases (˜2.5 h). The reaction mixture is cooled to room temperature, and the product extracted with diethyl ether (6×150 mL). The combined organic extracts are washed with brine (3×150 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give 1-bromo-3-fluoro-2-methoxybenzene as a brown oil. This product is of sufficient purity (≧95% by NMR spectroscopy) to use directly in the next synthetic step. 1H NMR (CDCl3): δ 3.95 (d, JH-F=1.5 Hz, 3H, OCH3), 6.88 (apparent t of d, JH-H=8.0 Hz, JH-F=5.5 Hz, 1H, H-5), 7.04 (d, JH-F=10.5 Hz, JH-H=8.0 Hz, JH-H=1.5 Hz, 1H, H-4), 7.30 (d of apparent t, JH-H=8.0 Hz, JH-H=1.5 Hz, JH-F=1.5 Hz, 1H, H-6). 19F{1H} NMR (CDCl3): δ −127.7 (s). 13C{1H} NMR (CDCl3): δ 61.4 (d, JC-F=5.0 Hz, OCH3), 116.2 (d, JC-F=19.5 Hz, C-4), 117.7 (d, JC-F=3.0 Hz, C-1), 124.5 (d, JC-F=8.0 Hz, C-5), 128.5 (d, JC-F=3.5 Hz, C-6), 145.7 (d, JC-F=12.5 Hz, C-2), 156.2 (d, JC-F=250.5 Hz, C-3).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:27]4[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][CH:28]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: O=C(O)c1ccccc1-c1ccc(Cl)cc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CC(C)C[C@H]2CN1C(=O)c1ccccc1-c1ccc(Cl)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 4′-chloro-biphenyl-2-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:35])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[CH:36]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:35])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:41]4[CH:42]=[CH:43][C:38]([CH:36]=[O:37])=[CH:39][CH:40]=4)=[CH:30][CH:29]=3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCc2ccc(Br)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2ccc(CCOc3cccc(C(NC(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)cc1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
(R)-quinuclidin-3-yl((3-(4-bromophenethoxy)phenyl)(phenyl)methyl)carbamate (0.40 g, 0.747 mmol), 4-formylphenylboronic acid (0.123 g, 0.822 mmol), and sodium carbonate (0.158 g, 1.494 mmol) were combined in toluene (9.94 mL) and water (2.48 mL). The mixture was degassed with nitrogen for 10 minutes. Tetrakis-(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol) was added, and the mixture heated at 120° C. for 30 minutes in a microwave. The mixture was filtered, and the filtrate partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a brown oil. The crude material was partially purified using a flash C18 cartridge eluting with 30-60% acetonitrile in water to afford a brown oil (0.174 g). The material was used directly in the next step with no further purification.