Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[O:5][CH2:6][CH2:7][NH:8][CH3:9].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].[F-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:9])[CH2:15][CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: CNCCOc1cc(F)cc(F)c1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCN1C(=O)c2ccccc2C1=O)CCOc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 78.6 %

Procedure:
A mixture of [2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amine (0.63 g, 3.4 mmol), 2-(3-bromo-propyl)-isoindole-1,3-dione (1.03 g, 3.8 mmol), 30% potassium fluoride on Celite® (1.35 g, 7 mmol) and acetonitrile (30 ml) was stirred for 20 hours at 50° C. The solvent was concentrated and the residue was dissolved in ethyl acetate. The Celite was filtered off, the solution was washed with water, then the organic phase was dried over magnesium sulfate and concentrated. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (97-3) to give 2-(3-{[2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amino}-propyl)-isoindole-1,3-dione (1 g, 78.6%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[CH3:21][C:22]1[CH:23]=[C:24]([NH2:37])[C:25]2[CH:26]=[N:27][N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]=2[CH:30]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:37][C:24]1[CH:23]=[C:22]([CH3:21])[CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: Cc1cc(N)c2cnn(-c3ccccc3)c2c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F

Procedure:
Prepared similarly to Example 14 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163) and 6-methyl-1-phenyl-1H-indazol-4-amine (Intermediate 10).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][CH:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([BH3-])#N.[Na+].O1CCCC1>C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)[CH2:8][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCCO3)c2ncnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCCO)CC2)c2ncnn12
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 4′-{[4-(1,5-dioxaspiro[5.5]undec-9-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.56 g), sodium cyanoborohydride (0.2 g), boron trifluoride-diethyl ether complex (0.4 mL) and tetrahydrofuran (15 mL) was stirred at 50° C. for 6 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 33%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[CH3:13].O>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1cccs1
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(O)(c1cccs1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 13.4 ml) in dry diethyl ether (25 ml) was added dropwise to a stirred solution of 2-bromothiazole (5 g) in diethyl ether (50 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiophene (3.85 g) in diethyl ether (25 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm to room temperature and was left stirring overnight. Water was added.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1>>[CH3:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13]1
Reactant: CN1CCCC(O)C1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CN1CCCC(Oc2ccc([N+](=O)[O-])cc2)C1

Procedure:
Using an analogous procedure to that described in Method 18, but starting from 4-nitrophenol and 3-hydroxy-1-methylpiperidine, the product was obtained. MS (MH+): 237.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 44 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (312 mg, 1.84 mmol), a white solid required compound (381 mg, 0.81 mmol, 44%) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)(C)(C)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>C(O)C.N1CCCCC1>[NH2:19][C:18]1[N:7]=[C:8]2[CH:12]=[CH:11][S:10][C:9]2=[CH:13][C:17]=1[C:16]#[N:20]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C=O
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cc2sccc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
(2-Formyl-thiophen-3-yl)-carbamic acid tert-butyl ester described in Preparation Example U-2 (500 mg, 2.20 mmol) and malononitrile (153 mg, 2.31 mmol) were dissolved in a solution of ethanol (10 mL) to which piperidine (catalytic amount) had been added, and the mixture was stirred for 1 hour under reflux. The reaction mixture was cooled to room temperature, the precipitated solid was filtered, and title compound (215 mg, 1.23 mmol, 56%) was obtained as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]=[CH:21][CH:22]=[CH:23][N:24]=1)=[O:11]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone and 2-chlorobenzoxazole. MS (ESI) 442 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12][C:13]#[CH:14].[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1I)[CH3:18]>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].[Cu]I.O1CCOCC1>[CH2:17]([C:19]1[C:20]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([CH:25]=[O:26])[NH:22][C:23]=1[C:14]#[C:13][CH2:12][Si:11]([CH3:16])([CH3:15])[CH3:10])[CH3:18]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Reactant: C#CC[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C#CC[Si](C)(C)C)[nH]c(C=O)c1C(=O)OC
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. Pd(Pt-Bu3)4 (18.4 mg, 0.040 mmol), Pd2(dba)3 (16.5 mg, 0.020 mmol), and CuI (4.6 mg, 0.020 mmol) were combined in a dry flask under N2 prior to evacuating the flask and refilling with argon. After the flask was charged with dioxane (4.0 mL), i-Pr2NEt (0.0675 mL, 0.48 mmol), trimethyl(prop-2-ynyl)silane (90.0 mg, 0.80 mmol), and methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (123.0 mg, 0.40 mmol) were added sequentially. The reaction was stirred overnight at 80° C. After the reaction was cooled to ambient temperature, it was filtered through a plug of silica gel and concentrated in vacuo. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.04 (s, 1H); 3.90 (s, 3H); 2.78 (q, J=7.5 Hz, 2H); 1.77 (s, 2H); 1.16 (t, J=7.5 Hz, 3H); 0.17 (s, 9H). HRMS (ES) exact mass calculated C15H22NO3Si (M+H): 292.1364. Found 292.1364
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[C:16]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:17]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([O:12][CH2:16][CH3:17])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15]
Reactant: N#Cc1cnc2cc(F)c(O)cc2c1Cl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc2c(Cl)c(C#N)cnc2cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. mixture of 4-chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile (185 mg, 0.83 mmol), triphenylphosphine (392 mg, 1.49 mmol) and ethanol (153 mg, 3.32 mmol) in 15 mL of tetrahydrofuran is added diethylazodicarboxylate (260 mg, 1.80 mmol). The reaction mixture is kept at 0° C. for 45 minutes then stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by flash column chromatography eluting with a gradient of 1 % ethyl acetate in hexane to 5% ethyl acetate in hexane provides 4-chloro-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, mp 165-166° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: Cn1cncc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cn1cncc1C(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methanone (1.30 g, 5.62 mmol, Intermediate 15: step b and tin(II)chloride dihydrate (6.54 g, 28.1 mmol) in EtOH (35 mL) was stirred at reflux for 1 hour, cooled to room temperature and evaporated in vacuo to remove most of the EtOH. The residue was poured into a 3 M aqueous NaOH/ice solution rinsing with EtOAc. The mixture was stirred at room temperature for 15 minutes then layers were separated. The aqueous layer was again extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1>CO.[Ni]>[NH2:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:15])=[CH:14][CH:13]=1
Reactant: CN(C)CCCOc1ccc(C#N)cc1
Agent: [Ni]
Solvent: CO
Product: CN(C)CCCOc1ccc(CN)cc1

Procedure:
4-(3-(Dimethylamino)propoxy)benzonitrile (300 mg) in methanol (20 mL) was treated with Raney nickel (wet, 1.5 g) under H2 (30 psi) for 4 hour. The insoluble material was filtered off and the filtrate was concentrated to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95.5 %

Procedure:
Ethyl [2-(7-methoxy-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (500 mg) was dissolved in a mixture of tetrahydrofuran (5 mL) and ethanol (5 mL). To the mixture was added 1M aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at room temperature for 50 min. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1M hydrochloric acid (3 mL). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (450 mg, 96%) as a pale yellow solid. MS 462 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([NH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]2[C:5]=1[NH:15][C:16](=[O:20])[C:17](=[O:18])[NH:14]2)([O-:3])=[O:2]
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-nitro-5-trifluoromethyl-1,2-phenylenediamine (0.560 g, 2.53 mmol) and oxalic acid (0.325 g, 2.58 mmol) in 2N HCl (8.5 mL) was refluxed for 6 h. The suspension was then cooled to r.t. and the solid filtered, washed with water (5.0 mL) and dried under vacuum to yield 0.502 (72%) of pure title compound as a yellow brown powder, m.p. 329°-332° C.; 1H NMR (DMSO-d6):7.640 (s, 1H), 8.111 (s, 1H), 11.414 (s, 1H), 12.432 (1H).
Reaction SMILES: [Na].C([O:5][CH2:6][CH:7]=[C:8]([CH3:21])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH3:17])(=O)C>CO>[CH3:21][C:8]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([CH3:18])[CH3:17])=[CH:7][CH2:6][OH:5]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CCC(C)=C(C)C
Agent: [Na]
Solvent: CO
Product: CC(=CCO)CCC=C(C)CCC(C)=C(C)C
Reaction time: 16 h

Procedure:
To a solution containing 2.3 g. of sodium in 100 ml. of absolute methanol, there were added 41.8 g. of 1-acetoxy-3,7,10,11-tetramethyl-2,6,10-dodecatriene. The reaction mixture was allowed to stand for 16 hours at room temperature under constant stirring. The reaction mixture was then evaporated under vacuum and poured onto a saturated aqueous sodium chloride solution. After this, the reaction mixture was exhaustively extracted with petroleum ether (b.p. 40°-45°). The combined petroleum ether extracts were dried over sodium sulfate and evaporated. Distillation produced 3,7,10,11-tetramethyl-2,6,10-dodecatrien-1-ol, b.p. 92-93°C./0.02 mmHg; nD20 = 1.4947.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:12][CH2:13][C:14]([F:17])([F:15])[F:16]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a stirred solution of methyl 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinate (0.80 g, 3.21 mmol, Step-1) in THF (10 mL) is added slowly lithium aluminum hydride (0.11 g, 3.21 mmol) at 0° C. The resulting mixture is stirred at rt for 1 hour. The reaction mixture is carefully quenched with 25% aqueous ammonia solution at 0° C. Then the mixture is diluted with DCM (50 mL) and celite is added to the mixture. After stirring at rt for 1 hour, the mixture is filtrated through a pad of Celite, and the filtrate is concentrated in vacuo to give 0.70 g (99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:11][O:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][C:17]2[C:18]([OH:30])=[C:19]3[C:23](=[C:24]([CH3:28])[C:25]=2[O:26][CH3:27])[CH2:22][O:21][C:20]3=[O:29])(=[O:10])[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C@H:33]([CH3:35])O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[CH2:38]([O:37][C:32](=[O:36])[CH:33]([O:10][P:8]([CH2:11][O:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:35])[CH3:39]
Reactant: CCOC(=O)[C@H](C)O
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)Oc1ccccc1)C(=O)OC2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)OP(=O)(COCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid monophenyl ester (18.5 mg, 0.040 mmol) and ethyl (S)-(−)-lactate (47 μL, 0.400 mmol) in pyridine (0.5 mL) was added PyBOP (32 mg, 0.060 mmol). The solution was stirred at room temperature for 1 hour, when an additional portion of PyBOP (21 mg, 0.040 mmol) was added. The solution was stirred for another hour and concentrated. The residue was purified by HPLC to provide 7.5 mg of the desired product as a clear oil. 1H NMR (300 MHz, CD3OD) δ 1.22 and 1.25 (t, 3H, J=7 Hz), 1.42 and 1.50 (d, 3H, J=7 Hz), 1.82 and 1.83 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.78 (s, 3H), 3.89 (d, 1H, J=8 Hz), 3.93-4.02 (m, 3H), 4.10-4.22 (m, 2H), 4.94-5.08 (m, 1H), 5.25 (s, 2H), 5.50-5.60 (m, 1H), 7.15-7.27 (m, 3H), 7.33-7.41 (m, 2H) ppm; 31P (121.4 MHz, CD3OD) δ 18.9, 20.3 ppm (diastereomers at phosphorus); MS (m/z) 549.2 [M+H]+, 571.3 [M+Na]+.
Reaction SMILES: Br[CH:2]([CH2:4][CH3:5])[CH3:3].[CH2:6]([O:13][NH:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][N:14]([CH:2]([CH3:3])[CH2:4][CH3:5])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCC(C)Br
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Product: CCC(C)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 36.7 %

Procedure:
Using the general method of Compound 42 Part B, 2-bromobutane (2.37 mL, 21.7 mmole) was reacted with 1-benzyloxy-3-phenylurea (4.87 g, 20.1 mmole) to provide 2.2 g of 1-benzyloxy-1-(1-methylpropyl)-3-phenylurea.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[C:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Reactant: O=C1CCCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc2n1N=C1CCCC1
Temperature: 165 °C
Yield: 65.1 %

Procedure:
The product of Example 304F (0.284 g, 0.61 mmol) and cyclopentanone (0.80 mL, 9.04 mmol) in N,N-dimethylacetamide (2 mL) were reacted at 130° C. for 40 minutes in a microwave reactor in a sealed tube. The reaction was concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.210 g, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.72 (m, 2 H) 1.87 (m, 2 H) 2.16 (m, 2 H) 2.71 (m, 2 H) 5.18 (s, 2 H) 7.31 (m, 11 H) 8.10 (d, J=8.46 Hz, 1 H) 16.22 (s, 1 H).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])[CH:5]=1)([O-])=O.[OH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH:23]([C:27]([OH:29])=[O:28])[CH2:24]2)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:13]1([C:11]([NH:10][C:6]2[CH:5]=[C:4]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH:23]([C:27]([OH:29])=[O:28])[CH2:24]4)=[CH:19][CH:18]=3)[CH:9]=[CH:8][N:7]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Reactant: O=C(Nc1cc([N+](=O)[O-])ccn1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A mixture of N-(4-nitropyridin-2-yl)cyclopropanecarboxamide (2.75 g, 13.3 mmol), 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2.55 g, 13.3 mmol) and Cs2CO3.(13.0 g, 39.8 mmol) in DMF (40 mL) was heated at 80° C. for 18 h. The reaction mixture was cooled to rt and concentrated. The residue was acidified to approximately pH 3 by the addition of 1N HCl. The precipitate was filtered and washed with water then hexane and dried under vacuum to provide 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.08 g, 87.2%) as a beige solid. LCMS: (FA) ES+ 353.2, ES− 351.3.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]3[C:15]([OH:17])=O)[S:8][C:4]=2[CH:3]=1.[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32][C:15]([C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[C:7]2[S:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:19]=[CH:18][C:5]=3[N:6]=2)=[O:17])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1
Product: O=C(N[C@H]1CCN(Cc2ccccc2)C1)[C@@H]1CCCCN1c1nc2ccc(Cl)cc2s1

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 45] and (3S)-1-benzylpyrrolidin-3-ylamine [see J. Med. Chem. (1989), 31(8), 1586-1590] to afford (2S)-N2-[(3S)-1-benzylpyrrolidin-3-yl]-1-(6-chloro-1,3-benzothiazol-2-yl)-2-piperidinecarboxamide as a solid.