Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN(C3SC=CN=3)C2)=NC=1CC.Br[C:34]1[N:39]=[CH:38][CH:37]=[CH:36][N:35]=1.[CH2:40]([O:42][C@H:43]1[CH2:47][NH:46][CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[C:58]([C:65]([F:68])([F:67])[F:66])=[N:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=2)=[C:51]([CH2:69][CH3:70])[N:50]=1)[CH3:41]>>[CH2:40]([O:42][C@H:43]1[CH2:47][N:46]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:45][C@H:44]1[NH:48][C:49]1[C:54]([CH2:55][CH3:56])=[N:53][C:52]([C:57]2[C:58]([C:65]([F:68])([F:67])[F:66])=[N:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=2)=[C:51]([CH2:69][CH3:70])[N:50]=1)[CH3:41]
Reactant: Brc1ncccn1
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Agent: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but substituting 2-bromopyrimidine and starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.30, 2.43, 2.69, 3.53, 3.78, 3.87, 3.99, 4.04, 4.27, 4.91, 5.27, 6.61, 6.97, 7.56, 8.41; IR (diffuse reflectance) 2398 (w), 2352 (w), 2307 (w), 2214 (w), 2173 (w), 1584 (s), 1569, 1549 (s), 1508 (s), 1476 (s), 1397, 1341, 1277, 1175, 1137 (s) cm−1 HRMS (ESI) calcd for C25H30N7O2F3+H1 518.2491. found 518.2479.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[C:24]([CH:26]=[CH2:27])[CH:23]=[C:22]4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12>[Pd].CO>[CH2:26]([C:24]1[CH:23]=[C:22]([C:28]2[NH:32][N:31]=[N:30][N:29]=2)[N:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:8]3[C:4]4=[N:5][CH:6]=[CH:7][C:2]([CH3:1])=[C:3]4[N:10]=[C:9]3[CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=2)[CH:25]=1)[CH3:27]
Reactant: C=Cc1cc(-c2nnn[nH]2)n(-c2ccc(Cn3c(CCC)nc4c(C)ccnc43)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-n2cc(CC)cc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-methyl-2-propyl-3-[4-[2-(1H-tetrazol-5-yl)-4-vinyl-1-pyrrolyl]benzyl]-3H-imidazo[4,5-b]pyridine (40 mg), 10% palladium on carbon (10 mg) and methanol (5 ml) was stirred at room temperature for 4 hours under hydrogen atmosphere (3 atm). After filtration, the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=5:1) to give 3-[4-[4-ethyl-2-(1H-tetrazol-5-yl)-1-pyrrolyl]benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=2[C:18]#[N:19])[CH2:10][CH2:9]1.C(=O)(O)O.[NH2:29][C:30]([NH2:32])=[NH:31]>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:17]=2[C:18]([NH2:19])=[N:31][C:30]([NH2:32])=[N:29]3)[CH2:12][CH2:13]1
Reactant: N#Cc1c(F)cccc1OCC1CCN(c2ccccc2Cl)CC1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(N)c2c(OCC3CCN(c4ccccc4Cl)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 28.9 %

Procedure:
2-[1-(2-Chlorophenyl)piperidin-4-ylmethoxy]-6-fluorobenzonitrile (0.28 g; 0.81 mmol) and guanidine carbonate (0.293 mg; 1.6 mmol) were heated at 140° C. in dimethylacetamide for 2 days, then cooled back to room temperature. The reaction mixture was diluted with water, stirred for 45 minutes, filtered, triturated with ethanol, and filtered. Solids were dried to afford 90 milligrams of 5-[1-(2-chlorophenyl)-piperidin-4-ylmethoxy)quinazoline-2,4-diamine (29% yield).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1>>[F:26][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:13][N:34]=[C:32]([C:31]4[CH:36]=[CH:37][C:28]([NH2:27])=[N:29][CH:30]=4)[N:33]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[C:17]([F:25])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(C(F)(F)F)c(F)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.16) (188 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (86 mg, 35%). MS (EI) 491.1 [(M)+]; mp 242° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.Cl.[C:30](OC1C(C(C)(C)C)=CC(O)=C(C=1C(C)C)C=O)(=[O:32])C>FC(F)(F)C(O)=O.O>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:30]=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)(C)C
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)C
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)(C)C
Temperature: 0 °C
Yield: 48 %

Procedure:
0.75 g of 4-acetoxy-3-t-butyl-5-isopropylphenol and hexamethylenetetramine were dissolved in 2.6 ml of trifluoroacetic acid and the solution was heated under reflux for 15 minutes. After cooling to 0° C., 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 1.5 hours. Additional 2 ml of 3N hydrochloric acid was added and the solution was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5% ethyl acetate) to give 0.40 g of a mixture of 5-acetoxy-4-t-butyl-2-hydroxy-6-isopropylbenzaldehyde and 5-acetoxy-6-t-butyl-2-hydroxy-4-isopropylbenzaldehyde as a pale yellow oil (yield 48%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14]([C:16]1[N:17]=[CH:18][NH:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][N:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[C:16]=1[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[O:22])[CH3:25]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(-c2ccccc2[N+](=O)[O-])c1C(=O)OCC
Yield: 81.7 %

Procedure:
To a solution of o-fluoronitrobenzene (106 g) and imidazole 4,5-dicarboxylic acid diethyl ester (106 g) in one liter of N,N-dimethyl formamide (DMF) was added anhydrous potassium carbonate (200 g). The reaction mixture was stirred vigorously for at least four hours. After removal of solvent under oil pump vacuum, the residue was treated with water, then extracted with chloroform (300 ml×3). The combined chloroform extracts were washed with water, dried by magnesium sulfate, then concentrated under vacuum to an oil. Upon treatment with ether, the oil was solidified and the product was obtained as a white solid (136 g, 81% yield). Recrystallized from chloroform-hexane, m.p. 93°-95° C.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.C([N:36]1[CH2:41][CH2:40][CH2:39][C:38](=O)[CH2:37]1)(OC(C)(C)C)=O.S([O-])([O-])(=O)=[O:44].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:44])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH:38]2[CH2:39][CH2:40][CH2:41][NH:36][CH2:37]2)[CH2:6]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@]1(C(=O)O)CN(C2CCCNC2)C[C@@H]1CCCB(O)O
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and N-BOC-piperidine-3-one (0.199 g, 1.0 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at 40° C. for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (276 mg, 1.3 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(piperidin-3-yl)pyrrolidine-3-carboxylic acid (138 mg, 68%) as an amber solid. NMR (D2O) δ 3.80-4.10 (m, 2 H), 3.60-3.80 (m, 2 H), 3.30-3.50 (m, 2 H), 3.00-3.15 (m, 1 H), 2.80-2.95 (m, 1 H), 2.45-2.60 (m, 1 H), 2.30 (m, 1 H), 1.95-2.10 (m, 1 H), 1.50-1.85 (m, 4 H), 1.10-1.40 (m, 3 H), 0.60-0.70 (m, 2 H). MS (m+1): 300.1; MS (M−H2O+1): 282.1.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[CH:9][C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:9]1[C:8](=[O:19])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2ccc(=O)n(C3CCCCC3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(Br)c(=O)n(C3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
8-Cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4 g, 14.5 mmol) was dissolved in dimethyl formamide (100 mL) and to this solution was added N-bromosuccinimide (3.9 g, 21.8 mmol) and benzoylperoxide (0.53 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 3 days then diluted with ethyl acetate and washed with water then twice with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 6-bromo-8-cyclohexyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one a cream colored solid (8 g). This crude intermediate was redissolved in CH2Cl2 and treated with 2-benzenesulfonyl-3-phenyl-oxaziridine (3.78 g, 14.5 mmol). The resulting solution was stirred at room temperature overnight then concentrated under reduced pressure and chromotographed on silica gel eluting with ethyl acetate. 6-Bromo-8-cyclohexyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was obtained as a colorless solid (3.72 g, 67%). 1H NMR: δ(400 MHz, CDCl3) 8.90 (s, 1H), 8.13 (s, 1H), 5.41 (br s, 1H), 2.96 (s, 3H), 2.58-1.70 (m, 2H), 1.87 (br d, J=13 Hz, 2H), 1.31-1.47 (m, 2H), 1.28 (t, J=3 Hz, 2H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[F:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[C:6]=1[OH:12].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C.CC(OC)(C)C>[F:4][C:5]1[CH:11]=[CH:10][C:9]([CH:20]=[O:21])=[C:7]([OH:8])[C:6]=1[OH:12]
Reactant: Oc1cccc(F)c1O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: O=Cc1ccc(F)c(O)c1O
Temperature: 25 °C
Yield: 19.6 %

Procedure:
Magnesium chloride (3.71 g, 33 mmol) was added portionwise at room temperature to a solution of 3-fluorocatechol (2 g, 15.6 mmol) in acetonitrile (20 mL), followed by triethylamine (13.4 mL, 97.5 mmol). Paraformaldehyde (3.16 g, 105.3 mmol) was then added to the stirred suspension and the mixture was heated at reflux for 5 hours. The mixture was cooled to room temperature then poured into a mixture of 5% HCl and TBME. The organic phase was separated, and the aqueous layer re-extracted with TBME. The combined organic extracts were washed with brine, dried over sodium sulphate and the solvent removed under reduced pressure. The crude mixture (˜1:1 starting material:product) was purified on normal silica in neat DCM followed by DCM/MeOH 96:4 and 90:10 to yield 478 mg of 28 still contaminated with 11.4% w/w of 3-fluorocatechol.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:35][CH2:36][CH2:37][CH2:38][OH:39])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[C:40](O)(=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCCCCC>[C:16]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40](=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]/[CH:48]=[CH:49]\[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
A solution of 1,3-dicyclohexylcarbodiimide (23.7 g) and 4-(N,N-dimethylamino)pyridine (15.9 g) in methylene chloride (200 ml) was added to a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (33.6 g) and z-octadeca-9-enoic acid (30 g) in methylene chloride (400 ml) under nitrogen at room temperature. On completion of reaction as evidenced by tic analysis the solution was diluted with hexane, filtered, concentrated and purified by dry column chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(z-octadeca-9-enoyloxy)propane as a free flowing pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][NH2:10].[C:13]([OH:23])(=[O:22])[C:14]1[C:15]([O:20][CH3:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.Cl.C[N:26](CCCN=C=NCC)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH:7]([NH:26][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:8](=[O:11])[CH3:9].[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][NH:10][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21]
Reactant: COc1ccccc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: COC(=O)CCCCC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCC(NC(=O)c1ccccc1OC)C(C)=O
Product: COC(=O)CCCCC(=O)CNC(=O)c1ccccc1OC
Reaction time: 36 h

Procedure:
Combine a mixture of 7-amino-6-oxo-heptanoic acid methyl ester and 5-amino-6-oxo-heptanoic acid methyl ester hydrochlorides (2.36 g, 11.3 mmol) with o-anisic acid (1.71 g, 11.3 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.16 g, 11.3 mmol), 1-hydroxybenzotriazole hydrate (11.3 mmol), N,N-diisopropylethylamine (5.88 mL, 33.8 mmol) in DMF and stir for 24-48 hours. Dilute the mixture with water and extract with EtOAc. Wash the combined extracts with brine and dry over Na2SO4 before concentrating. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for isolation of a mixture of 7-(2-methoxy-benzoylamino)-6-oxo-heptanoic acid methyl ester and 5-(2-methoxy-benzoylamino)-6-oxo-heptanoic acid methyl ester (3.45 g, 99%). MS (ES): (M+1)+ 308.1 m/z.
Reaction SMILES: [CH:1]1([CH:7]([O:50][CH3:51])[C:8]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:9]=2[CH2:10][N:11]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:12]2[N:13]=[N:14][N:15](CCO[Si](C(C)(C)C)(C)C)[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:73][CH2:72][CH2:71]1>>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:39])([F:41])[F:40])[CH:31]=1)[CH2:27][N:11]([CH2:10][C:9]1[CH:42]=[C:43]([C:46]([F:47])([F:48])[F:49])[CH:44]=[CH:45][C:8]=1[CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:50][CH3:51])[C:12]1[N:13]=[N:14][N:15]([CH:72]([OH:73])[CH3:71])[N:16]=1
Reactant: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCO[Si](C)(C)C(C)(C)C)n1)C1CCCCC1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C(C)O)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To N-(2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine (39.3 mg, 0.052 mmol) in THF (0.3 mL) at room temperature was added TBAF in THF (1.0 M, 0.1 mL, 0.1 mmol). The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-50% ethyl acetate in heptane) to afford a colorless oil (29.5 mg, 89%). 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.13 (m, 5H) 1.17 (d, J=11.20 Hz, 1H) 1.43-1.53 (m, 1H) 1.60 (s, 2H) 1.67-1.74 (m, J=2.90 Hz, 1H) 1.91 (d, J=12.86 Hz, 1H) 2.35-2.42 (m, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H) 4.12-4.16 (m, J=5.39 Hz, 2H) 4.62 (t, J=4.98 Hz, 2H) 4.72 (s, 2H) 4.75 (d, J=16.18 Hz, 1H) 4.88 (d, J=16.18 Hz, 1H) 7.36 (s, 1H) 7.49 (d, J=7.88 Hz, 1H) 7.56 (d, J=8.30 Hz, 1H) 7.67 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 639.2, Found: 640.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C[N:22]([CH:24]=O)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39]N(CC)CC)=[CH:32][CH:31]=1)=O>O.CCOC(C)=O>[CH2:6]([C:24]1[N:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:20][CH:19]=2)[CH:27]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH:3]([CH2:12][CH3:11])[CH2:4][CH3:5])=[CH:34][CH:35]=2)[N:22]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: COc1ccc(Oc2ccc(N)cc2)c2ccccc12
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(OCCCC(CC)CC)cc2)cn1-c1ccc(Oc2ccc(OC)c3ccccc23)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(4-methoxy-naphthalen-1-yloxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.3 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[ClH:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O.CN(C=O)C>[ClH:16].[ClH:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:27][CH2:26]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(NCCCBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 132.1 %

Procedure:
A mixture of benzyl (3-bromopropyl)aminoformate (495.2 g, 1.82 mol), prepared as in Example 6, 1-(2-methoxyphenyl)piperazine hydrochloride (377.9 g, 1.65 mol) and potassium carbonate (456.8 g, 3.31 mol) in 3L of DMF was stirred at 80° to 81° C. for 3.5 hours. The mixture was allowed to cool to room temperature and then poured into 20L of water. The mixture was extracted with ethyl acetate (3×4L). The combined ethyl acetate extracts were washed with water (2×1L) and saturated aqueous sodium chloride (1×1L), dried (Na2SO4) and treated with silica gel (200 g). The ethyl acetate was filtered and 11L of the filtrate was added slowly to 200 mL of 5.5N hydrochloric acid (2.75 mol) in ethanol at a rate such that the reaction temperature did not exceed 23° C. The mixture was aged at room temperature for 1 hour and filtered. The filtered residue was washed with ethyl acetate (3×500 mL), dried under a stream of air for 17 hours and then dried under reduced pressure at 60° C. to give benzyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylaminoformate dihydrochloride (496 g, 1.09 mol), m.p. 174°-176° C.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC(=S)c1ccccc1
Reactant: O=C(O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.5 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 10.05 g. (0.035 mole) of α, 2'-dichloro-4-biphenylylacetic acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14](Cl)=[O:15])=[CH:6][CH:5]=1>ClCCl>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9]/[C:10]/2=[CH:13]\[C:14]([NH2:2])=[O:15])=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2ccc(F)cc21
Yield: 90.6 %

Procedure:
A 29.6% aqueous ammonium hydroxide solution (17.6 mL, 134 mmol) was added dropwise to a stirred, chilled (ice bath) solution of (E)-2-(6-fluoro-1-indanylidene)acetyl chloride (14.1 g, 67 mmol) in dichloromethane (165 mL). After an hour, the resulting white precipitate was collected by filtration, dissolved in ethyl acetate (600 mL) and washed with water (3×300 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated in vacuo. The resulting off-white solid was washed with hexane, giving 11.6 g (91%) of (E)-2-(6-fluoro-1-indanylidene)acetamide, m.p., 180°-183° C.;