Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C(OCC)=O.S([N:27]=[N+:28]=[N-])(C1C=CC(C)=CC=1)(=O)=O>CCOCC.C(O)C>[N+:27](=[CH:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CCOC=O
Product: [N-]=[N+]=CC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
Sodium hydride (50% in oil, 0.53 g) is suspended in ether (20 ml), cooled to 0°, then treated dropwise with a mixture of acetophenone 1.2 ml) and ethyl formate (0.90 ml). The reaction is stirred 1 hr at 0° then overnight at 22°. The precipitate is filtered and washed well with ether to give a solid. The solid is suspended in ethanol (10 ml), cooled to 0°, then treated dropwise with tosyl azide (0.97 g). The reaction is stirred for 3 hrs, concentrated, dissolved in 1N sodium hydroxide and extracted with ether. The ether is washed with water, dried with sodium sulfate and concentrated to give the title compound.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([F:13])([F:24])[F:25])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 2-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a Waters Sunfire C8 column (30×75 mm) eluting with a gradient of acetonitrile and 0.1% trifluoroacetic acid in water at a flow rate of 50 mL/min. Fractions selected by mass spectrometry to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.27-1.38 (m, 2 H) 1.57-1.67 (m, 2 H) 2.27-2.32 (m, 3 H) 3.90-3.97 (m, 2 H) 5.99-6.02 (m, 1 H) 6.56-6.60 (m, 1 H) 7.53-7.62 (m, 2 H) 7.66-7.77 (m, 2 H); MS (ESI) positive ion 342 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH2:23]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:23][C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:14]2[O:13][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-c1ncco1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2ncco2)cc1

Procedure:
2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid 64 mg, 0.385 mmol) and 2-(oxazol-2-yl)thiophen-3-amine (64 mg, 0.385 mmol) according to protocol A. Retention time (min)=6.845, method [7], MS (ESI) 315.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.59 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.28-7.37 (m, 3H), 6.94-6.99 (m, 3H), 3.85 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 384. NMR: CDCl3: 1.99-2.05 (2 H, m, CH2), 2.80 (2 H, t, J 7.2, CH2), 2.81 (3 H, s, Me), 3.10-3.13 (2 H, m, CH2), 3.85-3.88 (4 H, m, CH2), 4.01-4.06 (6 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1H, s, Ar). MS: (ESI+): MH+ 487.20
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21]/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[CH3:27][O:26][C:24](=[O:25])[CH:23]=[CH:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)/C=C/CBr
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=CCN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a ice chilled solution of 1-benylpiperazine (25.0 g, 0.14 moles) in 140 mL dimethylformamide was added potassium carbonate (24.0 g, 1.25 eq.) and methyl 4-bromocrotonate (18.6 mL, 0.99 eq.). The solution was warmed to room temperature and stirred 24 h. The solution was filtered. Water was added and extracted with ethyl acetate. The organics were washed with water twice and brine, dried over sodium sulfate, filtered and evaportated to afford methyl-4-(4-benzylpiperazin-1-yl)but-2-enoate (35.2 g, 92%) as a brown-orange liquid. MS (ESI+) for m/z 275 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1.[C:13](OCC)(=[O:19])[C:14](OCC)=[O:15].CCN(CC)CC>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[C:14]([OH:15])[C:13]([OH:19])=[N:12]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2nc(O)c(O)nc2c1
Temperature: 150 °C
Yield: 69 %

Procedure:
A suspension of 4-methoxybenzene-1,2-diamine dihydrochloride in diethyl oxalate (8 eq) was treated with Et3N (2 eq) and then heated at 150° C. for 2 h. The mixture was cooled and filtered, and then the collected solid was washed with H2O and EtOH. The residue was dried to give the title compound (69%). MS (ES+) m/z 193 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH3:2].I[C:13]1[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][CH:14]=1>O.C(N)(CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:13]2[CH:25]=[CH:24][C:16]([CH2:17][CH2:18][NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCC(=O)NCCc1ccc(I)cc1
Reactant: C#Cc1ccc(OCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCC(C)N
Solvent: O
Product: CCOc1ccc(C#Cc2ccc(CCNC(=O)CC)cc2)cc1

Procedure:
150 mg (1.03 mmol) 1-ethoxy-4-ethynylbenzene, 327 mg (1.08 mmol) N-(4-iodophen-ethyl)propionamide (I47.2) and 36 mg (0.05 mmol) bis(triphenylphosphine)dichloro-palladium in 2.0 mL water and 1.5 mL sec-butylamine are stirred at r.t. over night and for additional 4 h at 30° C. The reaction mixture is partitioned between DCM and water. The solvent of the organic layer is evaporated in vacuo and the residue is purified by HPLC (MeOH/H2O/NH3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>O1CCOCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH:19]([CH2:22]O)[CH2:20]O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl.[NH2:32][C:33]1[NH:37][N:36]=[CH:35][C:34]=1[C:38]([OH:40])=[O:39]>ClCCl>[CH2:11]([O:18][C:19]1[CH:20]=[N:32][C:33]2[N:37]([N:36]=[CH:35][C:34]=2[C:38]([OH:40])=[O:39])[CH:22]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1[nH]ncc1C(=O)O
Reactant: OCC(CO)OCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(O)c1cnn2cc(OCc3ccccc3)cnc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 8.8 %

Procedure:
To solution of oxalyl chloride (0.6 mL, 6.87 mmol) in anhydrous dichloromethane (15 mL), cooled at −78° C., was added, dropwise, a solution of anhydrous dimethyl sulfoxide (1.2 mL, 16.5 mmol) in dichloromethane (2 mL) and the resulting mixture was stirred for 10 minutes at −78° C. A solution of 2-benzyloxy-1,3-propanediol (0.5 g, 2.75 mmol) in dichloromethane (2 mL) was then added dropwise at −78° C. and the reaction mixture was stirred for 15 minutes. Triethylamine (4.6 mL, 33 mmol) was then added dropwise at −78° C. and the resulting mixture was stirred for 1 hour. The cold bath was removed and an aqueous solution of hydrochloric acid (6 M, 6 mL, 36 mmol) was added, followed by 5-amino-1H-pyrazole-4-carboxylic acid (0.35 g, 2.75 mmol) and the reaction mixture was heated at 70° C. for 1 hour. The solid formed was collected by filtration, washed with water and dried under vacuum. The solid residue (0.53 g) was then washed with dichloromethane to give 65 mg (9% yield) of 6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. MS=270 [M+H]+.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][Sn](CCCC)(CCCC)CCCC)=[O:11])[CH2:2][CH2:3][CH3:4].[F:34][C:35]1[C:40]([F:41])=[CH:39][C:38]([F:42])=[C:37]([F:43])[C:36]=1O>C1COCC1>[CH2:30]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:26][CH2:27][CH2:28][CH3:29])[CH:6]=[CH:7][CH2:8][CH2:9][C:10]([O:12][C:36]1[C:35]([F:34])=[C:40]([F:41])[CH:39]=[C:38]([F:42])[C:37]=1[F:43])=[O:11])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](C=CCCC(=O)O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC
Reactant: Oc1c(F)c(F)cc(F)c1F
Solvent: C1CCOC1
Product: CCCC[Sn](C=CCCC(=O)Oc1c(F)c(F)cc(F)c1F)(CCCC)CCCC
Reaction time: 8 h

Procedure:
To a solution of tri-n-butylstannyl 5-(tri-n-butylstannyl)-4-pentenoate acid (1.0 equiv.) in anhydrous THF at room temperature is added dicyclohexy (1.2 equiv.) (Aldrich) and 2,3,5,6-tetrafluorophenol (1.2 equiv.) (Aldrich). The resulting solution is stirred overnight. The mixture is filtered, the filtrate is concentrated, and the residue is chromatographed to provide 2,3,5,6-tetrafluorophenyl 5-(tri-n-butylstannyl)-4-pentenoate.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=2)[CH:3]=1.Cl.[N:26]1[C:31]2[CH2:32][CH2:33][NH:34][CH2:35][C:30]=2[C:29](=[O:36])[NH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:11][C:9]1[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:15]=3)[CH:3]=[C:2]([N:34]3[CH2:33][CH2:32][C:31]4[N:26]=[CH:27][NH:28][C:29](=[O:36])[C:30]=4[CH2:35]3)[N:7]2[N:8]=1
Reactant: O=c1[nH]cnc2c1CNCC2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(N3CCc4nc[nH]c(=O)c4C3)n2n1
Temperature: 25 °C
Yield: 64.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A, 90 mg, 0.253 mmol), 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one hydrochloride (134 mg, 0.633 mmol), and N,N-diisopropylethylamine (98 mg, 0.757 mmol) in DMF (1.012 mL) was stirred at 100° C. for 90 min, then cooled to rt and maintained overnight. The mixture was filtered and the crude material recrystallized from hot methanol, providing the titled compound as a yellow solid (76.6 mg, 64%). 1H NMR (DMSO-d6) δ: 12.63 (br. s., 1H), 11.45 (s, 1H), 9.29 (s, 1H), 8.53-8.69 (m, 1H), 8.13 (s, 1H), 8.09 (dd, J=8.3, 0.8 Hz, 1H), 7.40 (s, 1H), 6.21 (s, 1H), 4.51 (s, 2H), 4.13 (t, J=5.7 Hz, 2H), 2.73 (s, 2H), 2.41 (s, 3H); ESI-MS: m/z 471.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[C:18](=[O:19])[N:17]([CH3:20])[C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=3[S:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH2:25]([O:27][CH:28]([O:32][CH2:33][CH3:34])[CH2:29][CH2:30]Cl)[CH3:26].C(OCC)(=O)C>CN(C)C=O.O>[CH2:25]([O:27][CH:28]([O:32][CH2:33][CH3:34])[CH2:29][CH2:30][C:13]1([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[C:18](=[O:19])[N:17]([CH3:20])[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]1)[CH3:26]
Reactant: COc1ccc(C2Sc3ccccc3N(C)C2=O)cc1OC
Reactant: CCOC(CCCl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCC1(c2ccc(OC)c(OC)c2)Sc2ccccc2N(C)C1=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.6 g) in dimethylformamide (5 ml), 3,4-dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (4.4 g) dissolved in dimethylformamide (15 ml) is added under nitrogen atmosphere and ice-cooling, and the mixture is stirred for 15 minutes at room temperature. β-Chloropropionaldehyde diethyl acetal (2.8 g) is added to the reaction mixture, and the mixture is stirred for 2.5 hours at 60° C. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with 1N sodium hydroxide and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4.4 g (71.5 %) of 2-(3,3-diethoxypropyl)-3,4-dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine as an oily form (compound No. 36, (IR: neat, cm-1) 1660, 1588, 1444, 1325, 1238, 750).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[N:7]=2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(CNc2cncc(Cl)n2)cc1
Product: Fc1ccc(CNc2cncc(-n3ccnc3)n2)cc1
Yield: 77.2 %

Procedure:
In a procedure analogous to example 2, reaction of 6-chloro-N-(4-fluorobenzyl)pyrazin-2-amine (240 mg, 1.01 mmol) and imidazole (76 mg, 1.11 mmol) furnished the product (210 mg, 65%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[CH3:10].I[C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[S:20])=[C:14](C)[C:13]=1C.[OH:23]CCN.O=S(Cl)Cl>>[OH:23][CH2:4][C:5]1([NH2:6])[CH2:3][CH2:2][CH2:8][CH2:7]1.[I:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:19]2[S:20][CH2:14][C:15]3([CH2:13][CH2:12][CH2:17][CH2:16]3)[NH:18]2)=[C:4]([CH3:9])[C:3]=1[CH3:10]
Reactant: Cc1c(N)ccc(I)c1C
Reactant: NCCO
Reactant: Cc1c(I)ccc(N=C=S)c1C
Solvent: O=S(Cl)Cl
Product: Cc1c(I)ccc(N=C2NC3(CCCC3)CS2)c1C
Product: NC1(CO)CCCC1

Procedure:
4-Iodo-2,3-dimethylaniline was converted to 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method A2b. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 4-iodo-2,3-dimethylphenyl isothiocyanate according to Method C2a to give 2-(4-iodo-2,3-dimethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-iodo-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 2-(4-cyano-2,3-dimethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=1[CH2:15][CH2:16][CH3:17].[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH2:18]([O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[C:7]([OH:14])[C:6]=2[CH2:15][CH2:16][CH3:17])=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCc1c(OCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOc2ccc(C(=O)OCC)cc2)ccc(C(C)=O)c1O

Procedure:
A mixture of 1.5 g of 1-[4-(2-bromoethoxy)-2-hydroxy-3- propylphenyl]ethanone 0.83 g of 4-hydroxybenzoic acid ethyl ester and 0.95 g of anhydrous potassium carbonate in 30 ml of anhydrous acetone and 10 ml of anhydrous DMF was stirred at reflux for 20 hours. The mixture was filtered and solvent was removed in vacuo. The residue was dissolved in ethyl acetic and washed with water. The extract was dried over magnesium sulfate) and concentrated in vacuo to an oil which was purified by HPLC using 25% ethyl acetate-hexane to give 1.3 g, m.p. 99-100 (75%) of 4-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-benzoic acid ethyl ester, the title compound. Analysis Calculated for C22H26O6 : C, 68.36; H, 6.78. Found: C, 68.39; H, 6.79.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH3:16][C:17]1[N:18]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]3)[CH:19]=[CH:20][N:21]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Product: Cc1nccn1CCOc1ccc2c(c1)CCCC2=O
Yield: 66 %

Procedure:
According to the method of Example 1, Step 2, 6-(β-chloroethoxy)-1-tetralone (0.208 g, 0.93 mmol) and 2-methylimidazole (0.137 g, 1.67 mmol) were reacted to provide the title compound (0.166 g, 66%) as a cream colored solid: CI-MS m/e 270 (M+), 271 (M+ +1); 1H-NMR (CDCl3): δ 7.94 (1H, d, J=8.0 Hz), 6.88 (2H, s), 6.72 (1H, dd, J=8.0 Hz, J=2.0 Hz), 6.60 (1H, d, J=2 Hz), 4.21 (4H, m), 2.85 (2H, t, J=6.0 Hz), 2.55 (2H, t, J=6.0 Hz), 2.41 (3H, s), 2.05 (2H, m).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1.C1CCCCC=1>CCO.[Pd]>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][C@@H:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@@H](CO)O3
Yield: 97.7 %

Procedure:
To a solution of (2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N2 for 18 h then cooled and filtered. The catalyst was rinsed with methanol and the filtrate was concentrated in vacuo to afford 0.113 g (98%) of the title alcohol as an off-white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[Cl:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[Cl:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:19]1[N:18]=[CH:17][C:8]2[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7]=2[N:20]=1)[C:26]([NH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]1)=[O:28]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3Cl)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-chlorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.77 (m, 15 H) 2.23 (s, 3 H) 2.84 (m, 2 H) 3.96-4.07 (t, J=12 Hz, 2 H) 4.66 (m, 1 H) 7.80 (dd, J=8.5, 1.9 Hz, 1 H) 8.00 (d, J=1.8 Hz, 1 H) 8.08 (d, J=8.6 Hz, 1 H) 8.19-8.33 (m, 2 H) 8.58 (s, 1 H). [M+H] calc'd for C26H32ClF2N7O2, 548; found 548.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].O.[OH-].[Na+].O=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:12]=O>CO.C(O)(=O)C>[C:14]1([C:11]2[N:2]=[CH:3][C:4](=[O:5])[NH:6][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC(N)=O
Reactant: O=CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=c1cnc(-c2ccccc2)c[nH]1
Temperature: -20 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a mixture of glycine amide hydrochloride (0.73 g), methanol (6.0 mL) and water (1.5 mL) were added a 12.5M aqueous sodium hydroxide solution (0.80 mL) and a solution of sodium hydroxide (0.26 g) in methanol (3.0 mL) at −30° C. Then, a solution of oxo(phenyl)acetaldehyde (1.0 g) in methanol (5.0 mL) was added, and the mixture was stirred at −20° C. for 2 hr and at room temperature for 1 hr. The reaction mixture was neutralized with acetic acid, and the resulting solid was collected by filtration and washed with water to give the title compound (0.86 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9](Cl)=[O:10].[NH2:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[C:9]([NH:19][C@H:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:21]1)=[O:10]
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Reactant: O=C(Cl)C(c1ccccc1F)c1ccccc1F
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C(c1ccccc1F)c1ccccc1F
Yield: 32.8 %

Procedure:
2,2-Bis(2-fluorophenyl)acetyl chloride (0.74 g) and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine (0.42 g) were reacted under the same conditions as in Example 53 to give (S)-2,2-bis(2-fluorophenyl)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)acetamide (0.29 g), melting point 107-108° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH2:8][CH2:9]Br)[CH:3]=1.C(OCC)(=O)[CH2:12][C:13]([O:15]CC)=[O:14].CC1ON=C(CCC(O)=O)C=1>>[C:13]([CH2:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)([OH:15])=[O:14]
Reactant: Cc1cc(CCCBr)no1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cc1cc(CCC(=O)O)no1
Product: Cc1cc(CCCCC(=O)O)no1
Yield: 56 %

Procedure:
3-(4-Carboxybutyl)-5-methylisoxazole was prepared from 5-methyl-3-(3-bromopropyl)isoxazole and diethyl malonate according to the procedure of part (c) above, and was obtained in 56% yield as a colorless solid, m.p. 58°-60° C. when recrystallized from carbon tetrachloride.