Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].C(N(CC)C1C=CC=CC=1)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][O:31][CH2:32][O:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COCCl
Reactant: COc1cc([N+](=O)[O-])c(CO)c(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: COCOCc1c([N+](=O)[O-])cc(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 2-hydroxymethyl-1-nitro-3,4,5-trimethoxybenzene (6.5 g, 26.7 mmol) and N,N-diethylaniline (9.96 g, 66.8 mmol) in dry chloroform (150 ml) was added dropwise chloromethylmethyl ether (4.28 g, 53.5 mmol) in an ice-bath. After stirring at room temperature overnight, the reaction mixture was washed successively with 1% hydrochloric acid, water, 10% sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent was removed by evaporation in vacuo and the residue was crystallized from hexane to give 7.62 g (99%) of 2-methoxymethoxymethyl-1-nitro-3,4,5-trimethoxybenzene, mp. 39-40 ° C. 1H-NMR (CDCl3): δ3.40 (3H, s, CH2OMe), 3.93 (6H, s, 2×OMe), 3.94 (3H, s, 1×OMe), 4.73 and 4.82 (each 2H, s, 2 ×CH2), 7.29 (1H, s, H-6). Analyses: Calculated for C12H17NO7 : C, 50.17; H, 5.59; N, 4.88. Found: C, 50.18; H, 5.92; N, 4.80.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])=[CH:5][CH:4]=2)[CH2:29][CH2:28]1
Reactant: CC1(O)CCNCC1
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(O)CCN(Cc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 140 mg (0.26 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.3a) in 1.5 mL DMF is added 61 mg (0.53 mmol) 4-hydroxy-4-methylpiperidine and 0.12 mL (0.66 mmol) N-ethyl-diisopropylamine at RT. The reaction mixture is stirred 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[CH:16]1[C:26](=[O:27])[CH2:25][C:19]2([CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[O:28])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH2:14][CH3:15])[C:8]=1[C:16]1[C:26](=[O:27])[CH2:25][C:19]2([CH2:18][C:17]=1[O:28][CH2:3][C:2]#[CH:1])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH3:6]
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)CC2(CCOCC2)CC1=O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOC1=C(c2c(CC)cc(C)cc2CC)C(=O)CC2(CCOCC2)C1

Procedure:
A solution of propargyl bromide (0.043 g, 0.36 mmol) in acetone (2 ml) is added dropwise to a mixture of 9-(2,6-diethyl-4-methylphenyl)-3-oxaspiro[5.5]undecane-8,10-dione (0.10 g, 0.3 mmol) and potassium carbonate (0.05 g, 0.36 mmol) in acetone (3 ml) and the reaction is refluxed overnight. The solvent is evaporated in vacuo, and the residue is taken up in ethyl acetate and washed with 2 N aqueous sodium hydroxide solution. The organic phase is concentrated in vacuo, and the residue is further purified by column chromatography on silica gel to give the desired compound as a colourless gum.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][NH:5][C:4]2[CH:10]=[CH:11][S:12][C:3]1=2.P(Cl)(Cl)([Cl:15])=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:15][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1c[nH]c2ccsc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
A stirred mixture of 7-oxo-4,7-dihydro-thieno[3,2-b]pyridine-6-carbonitrile (0.668 g, 3.8 mmol) and 6 ml of phosphorus oxychloride was heated to reflux for 2 h, and then cooled to room temperature. The residue was added to ice water and dichloromethane, and the resulting mixture was neutralized by addition of solid NaHCO3 carefully. The organic layer was separated, washed with H2O, dried over MgSO4, and concentrated in vacuum to give 0.526 g (71%) of a red-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 7.82 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 195.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: F[B-](F)(F)F
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[F:41][C:42]1[CH:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][N:43]=1>CO>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:49][CH2:48][C:46]4[CH:45]=[CH:44][N:43]=[C:42]([F:41])[CH:47]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Reactant: OCc1ccnc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
To a solution of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (117.7 mg, 0.265 mmol, prepared in Example 10b) and 1M solution of potassium tert-butoxide in tert-butanol (0.75 mL, 0.75 mmol) was added 2-Fluoro-4-pyridinemethanol (65.6 mg, 0.516 mmol, prepared in Example 15a). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (50 mM NH4OAc(aq), Acetonitrile system). The pure fractions were combined and the acetonitrile was removed in vacuo. The remaining aqueous solution was made basic with NaHCO3 and the free based product was extracted into EtOAc. The organic phase was concentrated in vacuo, and the solids were re-dissolved in acetonitrile/water and lyophilized to obtain pure product 4-[4-(2-Fluoro-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide. (19.0 mg, 13.5% yield). 1H NMR (CDCl3) 8.26 (d, 1H), 7.88 (s, 2H), 7.53 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.88 (s, 1H), 5.53 (s, 2H), 3.73-3.50 (m, 8H) ppm.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22]C(=O)C(C)(C)C)[CH2:15]1)=O.Cl>>[NH2:1][C@H:2]([C:3]1[N:13]([C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][OH:22])[CH2:15]2)[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[N:5]=1)[CH3:29]
Reactant: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Agent: Cl
Product: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1CCCN(CCO)C1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
A solution of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-aminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (200 mg, 0.49 mmol), in aqueous 6M HCl (8 mL) was refluxed for 30 min. After cooling to RT the volatiles were removed in vacuo and the resulting residue loaded in dioxane/water (1:1) onto an Isolute® SCX-2 cartridge. The cartridge was washed with dioxane/water (1:1), then dioxane and the product eluted with 10% 880 NH3 in dioxane. The fractions containing product were purified by column chromatography (Si—PCC, gradient 3-18% 2M NH3/MeOH in DCM) affording the title compound as a colourless gum (71.2 mg, 47%). LCMS (Method J): RT 0.39 min [M+H]+ 307.
Reaction SMILES: [CH2:1]([N:3]([C:27](=O)[C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20]C(=O)C(C)(C)C)[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].Cl[CH2:37][C:38]([N:40]([CH2:42][CH2:43][O:44][CH3:45])[CH3:41])=O>>[CH2:1]([N:3]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH2:37][CH2:38][N:40]([CH2:42][CH2:43][O:44][CH3:45])[CH3:41])=[CH:32][CH:33]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:12]=2[CH2:11]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 42.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.0 mg) was obtained.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.N1C=CC=CC=1>C(O)C>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:21][F:22])[C@@H:2]([OH:1])[C@H:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: Oc1ccccn1
Solvent: c1ccncc1
Solvent: CCO
Product: O[C@H]1[C@H](Oc2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2OC1(CF)CF
Yield: 20.3 %

Procedure:
A mixture of 0.42 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.21 g of 2-hydroxypyridine, 0.11 g of pyridine and 4 ml of ethanol was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.11 g of oily trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(2-pyridyloxy)-2H-1-benzopyran-3-ol represented by the following formula.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[CH3:13][S:14]([NH2:17])(=[O:16])=[O:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH:17][S:14]([CH3:13])(=[O:16])=[O:15])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: COc1cc(C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
2-Methoxy-4-methyl-benzoic acid (1.0 g. 6 mmol), methanesulphonamide (1.14 g. 12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.31 g. 12 mmol), 4-dimethylaminopyridine (1.47 g. 12 mmol) and DCM (50 mL) were combined and stirred at room temperature under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo and the residue suspended in water and acidified with aqueous potassium hydrogen sulphate (0.5 M). The mixture was extracted with EtOAc (1×30 mL). The organic layer was separated, washed with brine (2×20 mL), dried over sodium sulfate, filtered and evaporated to give a solid, which was triturated with hexane: diethyl ether (4:1) to yield the title compound as a white solid (0.92 g, 63%).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][F:29])=[CH:22][N:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[F:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:30]([OH:32])=[O:31])[NH2:8])=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N[C@@H](C[C@H](Cc1ccc(CCCF)cn1)C(=O)O)C(=O)O
Reaction time: 24 h

Procedure:
Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(3-fluoropropyl)pyridin-2-yl]methyl}-L-glutamate (68 mg, 0.13 mmol) was solved in 3 ml trifluoroacetic acid and stirred for 24 h. To the mixture was added toluene (10 ml) and the resulting solution was concentrated in vacuo. The crude product was purified by HPLC. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([O:35]CC)=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11].[OH-].[Na+]>>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:32][C:33]([OH:35])=[O:34])[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:30])=[CH:24][CH:23]=3)=[N:17][C:16]=2[CH:31]=1)=[O:11]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)c1ccc(NCc2nc3cc(C(=O)N(CC(=O)O)c4ccccn4)ccc3s2)cc1

Procedure:
Prepared analogously to Example 10 from 2-[N-(4-amidinophenyl)-aminomethyl]-benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)-amide-dihydrochloride and sodium hydroxide solution.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1>>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:22])([CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][C:15]=1[Br:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(C)(C)c1ccc(N)cc1
Product: CCOC(=O)C(C)(C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-aminophenyl)-2-methylpropionate (4.74 g in 40 mL dry methylene chloride) at 0° C. was added 4.08 g of N-bromosuccinimide and the mixture stirred at low temperature. After 1 hour, the mixture was warmed to room temperature and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane:ethyl acetate, 9:1; then 8:2) gave the title compound, 5.46 g.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>C(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:9]([NH:8][CH2:7][C@@H:6]1[C@H:2]([OH:1])[CH2:3][NH:4][CH2:5]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CNC(=O)C(F)(F)F)[C@H](O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CNC[C@H]1O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1,1-dimethylethyl(3S,4S)-3-hydroxy-4-{[(trifluoroacetyl)amino]methyl}-1-pyrrolidinecarboxylate (0.192 g, 0.615 mmol) was dissolved in methylene chloride (5 mL). HCl in dioxane (1.0 mL, 4.0 mmol) was added and the solution stirred at ambient temperature for 2 hours. The solvent was removed under reduced pressure. (0.137 g, quant.) LCMS: m/z 213.2 (MH+).
Reaction SMILES: Br[CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=O.[CH:25]([N:28]1[CH2:33][CH2:32][N:31]([C:34](=[S:36])[NH2:35])[CH2:30][CH2:29]1)([CH3:27])[CH3:26]>CCO>[F:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:35]=[C:34]([N:31]2[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]2)[S:36][C:2]=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19]([CH:22]([CH3:24])[CH3:23])=[N:20][N:21]=2)[N:18]=1
Reactant: CC(C)N1CCN(C(N)=S)CC1
Reactant: CC(C)c1nnc2ccc(C(Br)C(=O)c3ccc(F)cc3F)nn12
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3sc(N4CCN(C(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.49 g, 1.24 mmol, Preparation #A.2) in EtOH (10 μL) was added 4-isopropylpiperazine-1-carbothioamide (0.21 g, 1.12 mmol, Preparation #AO.1.1). The reaction mixture was stirred at about 40° C. for about 2.5 h. The reaction mixture was cooled to ambient temperature and the solvent was removed under reduced pressure. DCM (35 mL) and water (20 mL) were added. The layers were partitioned and the organic layer was washed with additional water (200 mL). The organic layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude residue was purified by silica gel column chromatography DCM/MeOH (gradient from 100:0 to 90:10) to afford the title compound (0.34 g, 56%) as a yellow solid: LC/MS (Table 1, Method a) Rt=2.06 min; MS m/z: 484.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:3][CH:2]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:3][CH:2]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1cc(CN[C@H]2CCCc3ccccc32)cc(Oc2ccncc2)c1
Yield: 84.3 %

Procedure:
3-(4-Pyridinyloxy)benzaldehyde (0.85 g, 4.27 mmol), prepared according to J. Chem. Soc. Perkin Trans 2 (1987) 1867, and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (0.63 g, 4.29 mmol) were combined in ethanol (10 mL), briefly heated and the solvent removed under reduced pressure. This process was repeated twice more. The residual oil was dissolved in ethanol (5 mL) and stirred with sodium borohydride (0.16 g, 4.23 mmol) overnight at room temperature. The reaction mixture was quenched with water (10 mL) and diluted with diethyl ether (50 mL). The diethyl ether was washed with saturated NaHCO3 solution (3×10 mL), brine (10 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide the title compound as a thick orange liquid (1.19 g, 85% yield).
Reaction SMILES: I[C:2]1[C:7]([C@H:8]([CH3:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:6]([I:15])[N:5]=[CH:4][N:3]=1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)C(C)C)(C)C>CO>[I:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:26]2[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]2)[C:7]=1[C@@H:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)C[C@@H](C)c1c(I)ncnc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Into a solution of (R)-methyl 3-(4,6-diiodopyrimidin-5-yl)butanoate (212 g, 491 mmol) and Boc-piperazine (101 g, 540 mmol) in methanol (424 mL) was added N,N-diisopropylethylamine (94.3 mL, 540 mmol). The mixture was heated at 60° C. for 24 h. Methanol was distilled off under reduced pressure below 40° C. To the mixture was added 318 mL of tetrahydrofuran. The above solvent swap process was repeated twice. To the mixture were added 424 mL of tetrahydrofuran, 212 mL of saturated aqueous ammonium chloride, and 21.2 mL of water. The organic layer was washed with 212 mL (1.00 vol.) of saturated aqueous ammonium chloride. This tetrahydrofuran solution was used for next step without further purification (91% weight assay yield). 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 3.80-3.67 (m, 1H), 3.65 (s, 3H), 3.60-3.56 (m, 4H), 3.21-3.18 (m, 4H), 3.14 (dd, J=16.2, 9.0 Hz, 1H), 2.81 (dd, J=16.2, 5.7 Hz, 1H), 1.48 (s, 9H), 1.47 (d, J=7.2 Hz, 3H). HRMS calcd. For C18H28IN4O4 [M+H]+: 491.1150. found 491.1154.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])[CH3:3].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:17]2[CH:18]=[C:19]([NH2:23])[N:20]=[CH:21][N:22]=2)=[CH:7][C:6]=1[C:12]([F:14])([F:13])[F:15])[CH3:1]
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: Nc1cc(Cl)ncn1
Product: CN(C)Cc1ccc(Nc2cc(N)ncn2)cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 5 h

Procedure:
The title compound is prepared as described in Example 152A but using 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (218 mg, 1.46 mmol, 1 eq.), 6-chloro-pyrimidin-4-ylamine, and stirring the reaction mixture for 5 h at 150° C. The crude product is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 92:8) to afford the title compound as a white solid. ESI-MS: 312.1 [MH]+; tR=1.20 min (purity: 100%, gradient J); TLC: Rf=0.16 (DCM/MeOH+1% NH3aq, 92:8).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])=[CH:9][N:8]=[CH:7]1>C1COCC1>[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([NH:14][C:2](=[O:3])[O:4][CH3:5])[CH:15]=[CH:16][CH:17]=2)=[CH:9][N:8]=[CH:7]1
Reactant: COC(=O)Cl
Reactant: Nc1cccc(-c2cnco2)c1
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(-c2cnco2)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
Methyl chloroformate (1.67 mL, 21.54 mmol) was slowly added to a 0° C. solution of 3-(oxazol-5-yl)aniline (2.30 gm, 14.36 mmol) and TEA (4.00 mL, 28.70 mmol) in THF (65 mL). The ice bath was removed and the reaction mixture was stirred at rt. After 2.5 h the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic phase was isolated, washed with 1 N HCl (2×) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, methyl 3-(oxazol-5-yl)phenylcarbamate, (1.34 gm, 6.14 mmol, 43% yield) as a white solid. Anal. Calcd. for C11H10N2O3 m/z 218.1, found: 219.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[C:20]([O:8][CH2:9][CH2:10][O:11][CH:12]([CH3:19])[CH2:13][CH:14]1[O:15][CH2:16][CH2:17][O:18]1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: CC(CC1OCCO1)OCCO
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(C)CC1OCCO1

Procedure:
Following the above procedure, the monomer was prepared using 22 g triethylamine, 35.2 g 2-[2-(2-hydroxyethoxy)-propyl]-1,3-dioxolane, 23.22 g methacryloyl chloride, and 180 ml methylene chloride. The product was purified by vacuum distillation at 93.2° C. under 0.2 mm Hg pressure.