Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][NH:19]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]1[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 100 °C
Yield: 79 %

Procedure:
In a tube, a mixture of 1d (0.299 g, 1.0 mmol), 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) in toluene (10 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.046 g, 0.05 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.168 g, 1.5 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 2 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed to yield the title product (0.278 g, 0.79 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 3.84 (t, J=6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H).
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[NH:6][C:5]1=[S:24])[CH:2]=[CH2:3].[C:25]([NH:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)(=[O:27])[CH3:26].[OH-].[K+].[I-].[Na+]>C(O)C.O>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[S:24][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:36][CH:35]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: C=CCn1c(=S)[nH]c2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCn1c(SCc2ccc(NC(C)=O)cc2)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2

Procedure:
A mixture of 3-allyl-2-thioxo-2,3-dihydro-1H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (5, 0.100 g, 0.295 mmol), 4-acetamidobenzyl chloride (0.060 g, 0.325 mmol), potassium hydroxide (0.025 g, 0.443 mmol), and catalytic sodium iodide (4.43 mg, 0.030 mmol) in ethanol (1.738 ml) was refluxed for 24 h. 1 ml of water was added to the cooled reaction and the mixture was extracted with EtOAc 2×. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.95, 8.10, 7.51, 7.39-7.32, 5.85, 5.20, 5.13, 4.59-4.56, 3.02, 2.02, 1.70-1.67, 1.60-1.50, 1.28; MS (EI) m/z 486 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[CH:11][C:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH:24]=O.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[C:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:24][C:23]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:22]=3[CH3:21])=[CH:7][CH:6]=2)[N:9]=[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=1)#[N:14]
Reactant: Cc1cccc(C)c1C=O
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cccc(C)c1CNc1ccc(-n2nc(-c3cccnc3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-3-(3-pyridyl)-5-cyanopyrazole (130 mg, 0.5 mmol) and 2,6-dimethylbenzaldehyde (0.9 g) in acetic acid (2 mL) and MeOH (5 mL) at room temperature was added sodium cyanoborohydride (79 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 18 hr and then concentrated under a stream of nitrogen, diluted with water, extracted into ethyl acetate, washed with sodium bicarbonate solution, water and dried (MgSO4). The residue obtained on concentration was flash chromatographed on silica gel (elution with a gradient of 15-25% EtOAc in CH2Cl2) providing the title compound (142 mg, 75%). NMR (CDCl3, 400 MHz): 9.1 (s, 1H); 8.7 (br, 1H); 8.3 (d, 1H); 7.6 (d, 2H), 7.5 (m, 1H), 7.35 (s, 1H); 7.2 (m, 1H), 7.1 (overlapping m, 2H), 6.8 (d, 2H), 4.3 (s, 2H), 2.4 (s, 6H).
Reaction SMILES: FC(F)(F)C1C=[C:5]([CH2:13][O:14]CC#N)C=C(C(F)(F)F)C=1.[Li][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC.C1(CC2C=CC=CC=2)C=CC=CC=1.Cl>CCCCCC.C(OCC)C.C(OCC)(=O)C>[C:22]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:13](=[O:14])[CH3:5])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [Li]C(c1ccccc1)c1ccccc1
Reactant: N#CCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccc(Cc2ccccc2)cc1
Product: CC(=O)C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a cooled (-80° C.) solution of ((3,5-bis(trifluoromethyl)phenyl)methyloxy)acetonitrile (0.51 g; Example 1a, Method B(i) was added 0.42M lithio diphenylmethane (10 ml; prepared by addition of 2.5M n-butyl lithium in hexane (10 ml) to a cooled (-80° C.) solution of diphenylmethane (4.2 g) in diethyl ether (5 ml), followed by warming to room temperature for 3 hours). The solution was warmed to room temperature for 0.5h and then 1M-hydrochloric acid (10 ml) and ethyl acetate were added and the organic phase washed with saturated brine and dried (MgSO4). After evaporation in vacuo the residue was chromatographed on silica gel (eluting with 5% ethyl acetate in hexane ) to give 1-(3,5-bis(triflouromethyl)phenyl)methyloxy)-3,3-diphenyl acetone as an oil which gave an identical 1H NMR spectrum to the material prepared by Method A.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cnc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 197.7 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-methyl-1H-imidazol-4-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (292 mg, 0.6134 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (8 mL, 3 mol/L). The reaction was stirred overnight at rt and concentrated in vacuo to give the title compound as a yellow solid (250 mg, 98.82%).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][CH2:36][S:37][CH3:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][CH2:36][S:37][CH3:38])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CSCC[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](CCSC)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.90 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 66-2 (7.48 mmol, crude form) as starting materials, respectively 1.17 g (Isomer A, pale yellow amorphous) and 1.49 g (Isomer B, pale yellow amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:26]1[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[C:28]([CH3:39])[CH:27]=1)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH2:24][C:26]2[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[C:28]([CH3:39])[CH:27]=2)=[CH:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2ccn(C(c3ccccc3)c3ccccc3)c2c1
Reactant: COC(=O)COc1c(C)cc(C=O)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cc2cn(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc(C)c1OCC(=O)O
Temperature: 0 °C
Yield: 89 %

Procedure:
To 1-benzhydryl-6-chloro-1H-indole (1.0 eq) and methyl 2-(4-formyl-2,6-dimethylphenoxy)acetate (0.6 eq) in CH2Cl2 (0.1M) at 0° C. was added neat triethysilane (3 eq) followed by triflouroacetic acid (3 eq). After 10 minutes at 0° C. the reaction was warmed to room temperature and stirred until the initially formed spot by TLC yields a new spot. The reaction was then quenched by the addition of saturated sodium bicarbonate, diluted with CH2Cl2 and washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and purified by column chromatography to yield 89% of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:7]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(=O)NCc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 2-aminoisonicotinic acid (2.76 g, 20.0 mmol) in N,N-dimethylformamide (60 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.00 g, 26.0 mmol) and N,N-diisopropylethylamine (10 mL, 57.7 mmol). The resulting solution was stirred for 30 minutes at ambient temperature followed by the addition of 1-hydroxybenzotriazole (3.24 g, 24.0 mmol) and benzylamine (3.2 mL, 29.3 mmol). The reaction mixture was stirred for 72 hours at ambient temperature, diluted with water (30 mL) and extracted with ethyl acetate (200 mL×4). The combined organic layers were washed with brine (30 mL), dried over anhydrous sulphate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and hexanes (in a 1:10 ratio), filtered and dried in vacuo to give 2-amino-N-benzylisonicotinamide as a colorless solid (1.97 g, 43%): NMR (300 MHz, CDCl3) δ 8.11-8.09 (m, 1H), 7.37-7.27 (m, 5H), 6.88-6.82 (m, 2H), 6.42 (br s, 1H), 4.60 (d, J=5.7 Hz, 2H); MS (ES+) m/z 228.5 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F: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]([OH:35])=O)[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][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:35])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and tert-butyl(3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (Example C2) the title compound is obtained as pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH2:23]([NH2:25])[CH3:24]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH2:23][CH3:24])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: FC(F)(F)c1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CCN
Product: CCNc1nc(Cl)nc2c1COCC2c1ccc(C(F)(F)F)cc1

Procedure:
2,4-dichloro-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Z) was reacted as described in Preparation Xa with ethanamine to give 2-chloro-N-ethyl-8-(4-(trifluoromethyl)phenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Za). LC-MS (M+H)+=358.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:3]=1.C(Cl)(=O)C>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:14][C:12](=[O:13])[CH2:11]2
Reactant: O=C(O)Cc1cc(Br)ccc1C(=O)O
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: O=C1Cc2cc(Br)ccc2C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 4-bromo-2-carboxymethyl-benzoic acid (product of step i)) (11.0 g) in acetone (200 mL) was treated with acetyl chloride (13.3 g) and the solution stirred at room temperature for 17 hours. The reaction mixture was evaporated then azeotroped with toluene to yield the sub-title compound (9.8 g).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][N:10]2C(OC(C)(C)C)=O)=[O:6])[NH2:4].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1.C(O)(C(F)(F)F)=O>O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[C@H:8]12[CH2:13][C@H:11]([NH:10][CH2:9]1)[CH2:12][N:7]2[C:5]([C@@H:3]([NH:4][C:32]([C:24]1[NH:23][C:31]2[C:26]([CH:25]=1)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:33])[C:2]([CH3:1])([CH3:21])[CH3:22])=[O:6]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)[C@@H](N)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a 500 ml flask was added 1,1-dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (17.1 g, 54.9 mmol), 1H-indole-2-carboxylic acid (10.62 g, 65.9 mmol), HOBt (10.09 g, 65.9 mmol) and EDC (25.3 g, 132 mmol) followed by CH2Cl2 (366 ml) and NMM (24.15 ml, 220 mmol). The mixture was stirred for 18 h. The reaction was diluted with water (150 ml) and sat. Na2CO3 (150 ml). Stirring was continued for an additional 0.5 h then the two layers were separated. The organic solution was washed with sat. NaHCO3, 1N HCl, sat. NaHCO3, and brine. The organic layer was passed over a phase separator and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 ml). To the solution was added TFA (25 ml, 324 mmol). Stirring continued for 2 h then the solution was concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 then washed twice with 2N HCl. The acidic solution was made basic and extracted with CH2Cl2. The organics were dried and concentrated to afford a brown residue. The residue was purified by reverse phase chromatography on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 3 CV water, the 0-50% ACN/Water over 10 CV. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the resulting aqueous layer was saturated with NaCl and extracted three times with CH2Cl2. The combined CH2Cl2 extracts were combined, dried and concentrated to afford the desired product (10 g, 28.2 mmol) as an off white solid. LCMS (m/z): 355.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16][CH:17]=[CH2:18])=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: C=CCCC(O)c1c(C)noc1-c1ccc(Br)cc1
Reactant: Ic1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccccc1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-pent-4-en-1-ol and iodobenzene.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:13][Br:14]>>[Br:13][Br:14].[CH2:12]([Br:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCC
Agent: BrBr
Product: CCCCCCCCCCCCBr

Procedure:
Pressurized dodecane liquid is mixed with bromine in a 10:1 molar ratio. The mixture is passed through a tubular reactor held at 250° C. 100% bromine conversion is obtained with 90% selectivity to dodecylbromide.
Reaction SMILES: COC1C=CC(C[N:10]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([S:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:19]=2)[S:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:25][O:24][C:22]1[N:21]=[C:20]([S:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:19]=[C:18]([NH:10][S:11]([N:14]2[CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])[CH:23]=1
Reactant: COc1ccc(CN(c2cc(OC)nc(SCCc3ccccc3)n2)S(=O)(=O)N2CCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NS(=O)(=O)N2CCC2)nc(SCCc2ccccc2)n1

Procedure:
A solution of N-[(4-methoxyphenyl)methyl]-N-[6-methoxy-2-[(2-phenylethyl)thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the product of step iii, 0.17 g) in DCM (1 ml) and TFA (2 ml) was stirred at room temperature for 18 h. The solvent was evaporated under reduced pressure. The residue was recrystallised from EtOAc and iso-hexane to give the title product as a white solid. Yield: 50 mg.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[C:21]([Cl:29])[CH:20]=1)[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CC(C)=O>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:38])=[O:2])[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:30])[NH:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:20][C:21]=1[Cl:29])[CH:27]=[CH2:28]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OC)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C[C@H](NC(=O)Cc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1Cl
Temperature: 0 °C
Yield: 52.3 %

Procedure:
4-Allyloxy-3-chloro-phenylacetyl-(L)-phenylalanyl-(L)-phenylalanine methyl ester (5.3 g) was suspended in acetone (40 ml) to which was added aqueous sodium hydroxide (1 M, 20.0 ml) and the whole was heated to effect solution. After the solution had been cooled to 0° C., the pH was adjusted to 2-3 using aqueous hydrochloric acid (3 M) and the whole was extracted with ethyl acetate (80 ml). The extract was dried (anhydrous sodium sulphate) and the solvent was evaporated at reduced pressure to leave a small volume of material. Light petroleum (b.p. 80°-100° C.) was added to precipitate the solid (3.5 g) of m.p. 180°-186° C. After recrystallisation from ethyl acetate/light petroleum (b.p. 80°-100° C.), the above-named product (2.7 g), m.p. 183°-186° C., was obtained.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([O:25]C)=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].O>C(O)C>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)O)c1
Yield: 81.7 %

Procedure:
A mixture of 40.5 g of 3-(tetradecyloxy)benzeneacetic acid, methyl ester, 18.8 g of potassium hydroxide, 15 ml of water and 300 ml of ethyl alcohol is refluxed for 4 hours. The solvent is removed and the residue partitioned between chloroform and dilute hydrochloric acid. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 31.8 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:17])[F:16])[C:11](=[O:19])[N:10]([CH2:20][C:21]([O:23]C)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>CO.O.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:17])([F:16])[F:18])[C:11](=[O:19])[N:10]([CH2:20][C:21]([OH:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 76A, 260 mg (0.72 mmol) were dissolved in 5 ml of methanol and admixed with 2.87 ml (2.87 mmol) of a 1M solution of lithium hydroxide in water. The mixture was stirred at RT for 1 h, then acidified with 1N hydrochloric acid and diluted with DMSO. The entire solution was purified by preparative HPLC (Method 10). This gave 215 mg (86% of theory) of the title compound.
Reaction SMILES: [N:1]([CH:4]([C@H:6]1[C@H:9]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[NH:8][C:7]1=[O:16])[CH3:5])=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH:4]([C@H:6]1[C@H:9]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[NH:8][C:7]1=[O:16])[CH3:5]
Reactant: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)N
Yield: 90.1 %

Procedure:
Trans-3-(1-azidoethyl)-4-(2'-acetoxyethyl)-2-azetidinone (0.824 g, 0.00364 mole), is dissolved in EtOAc and hydrogenated with 0.824 g, 10% Pd/C under 40 lbs of H2 for 1 hr. IR shows disappearance of N3 absorption. The catalyst is filtered off and the solution is evaporated in vacuo to give 0.658 g, (0.00328 mole, 90% yield) of the product.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.2 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purin-6-amine (6 mg, 85% pure) was dissolved in methanol (1 mL), treated with 4N hydrogen chloride in 1,4-dioxane (0.5 mL) and stirred for 5 hours at room temperature. The mixture was stripped to dryness to give the title compound (77.8:10.8 by LCMS) as a colourless gum (8 mg).