Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:9]2[S:14][C:13]3[CH:15]=[CH:16][C:17]4[C:22]([C:12]=3[NH:11][C:10]2=[O:23])=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.CC(C)=O>O>[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][N:11]1[C:10](=[O:23])[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=2)[S:14][C:13]2[CH:15]=[CH:16][C:17]3[C:22]([C:12]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCCN1C(=O)C(c2cccc(C(F)(F)F)c2)Sc2ccc3ccccc3c21

Procedure:
A mixture of 3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (18.0 g), potassium carbonate (24.2 g), 3-(dimethylamino)propyl chloride hydrochloride (9.5 g), acetone (400 ml) and water (4 ml) is refluxed for 48 hours. The insoluble materials are filtered off and acetone is distilled off, and to the residue are added ethanol (200 ml) and 10% hydrochloric acid (100 ml), and the mixture is refluxed for one hour. After ethanol is distilled off and the insoluble materials are filtered off, the resulting mixture is made alkaline with sodium hydrogen carbonate and extracted with ethyl acetate. The extract is distilled to remove the solvent to give 1-[3-(dimethylamino)propyl]-3-(3-trifluoromethylphenyl)-1H-naphtho[2,1-b][1,4]-thiazin-2(3H)-one as oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])=[O:21])=[CH:17][N:16]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2,2,2-trifluoroethylamine 77 μL, 0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (213 mg, 84%) as a white solid. MS: m/e=392.2 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C:21]1[C:22](=[O:38])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=2[O:36][CH3:37])[CH:24]=[CH:25][CH:26]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:22]2=[O:38])=[C:28]([O:36][CH3:37])[CH:29]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
25 g (48 mmol) of the compound from Example 22A are dissolved in 800 ml of a 1:1 mixture of ethanol and ethyl acetate, and 18 g (286 mmol) of ammonium formate and 800 mg of palladium on carbon are added. The mixture is heated at 80° C. After 60 min, the mixture is allowed to cool and filtered through silica gel. The filter cake is washed with ethyl acetate, and the filtrate is concentrated to dryness under reduced pressure. This gives 27 g (98% of theory) of the desired product.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]1>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:31]3[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CCOC(=O)C1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.45 g, 1.57 mmol) was dissolved in dichloromethane (15 ml), then diisopropylethylamine (0.6 ml, 3.53 mmol) and ethyl azetidine-3-carboxylate hydrochloride (I-147) (0.55 g) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant).
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=3)[N:11]([CH3:32])[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH3:32][N:11]1[C:10]2[CH2:9][NH:8][CH2:20][CH2:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:16]=2
Reactant: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CNCC1)(C(C)C)C(C)C

Procedure:
A solution of 9-methyl-6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (175 mg) and 0.5 mL of trifluoroacetic acid in 3 mL dichloromethane was stirred for 4 h. The solvent was removed to afford 9-methyl-6-triisopropylsilanyloxy-2,3,4,9-tetrahydro-1H-β-carboline trifluoroacetate (125 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[F:33][C:28]([F:34])([C:29]([F:32])([F:31])[F:30])[CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
A solution of 4-hydroxybenzaldehyde (2 g, 16.7 mmol) in DMF (33 mL) was stirred as solid potassium carbonate (4.1 g, 29.7 mmol) was added, and the reaction mixture was then stirred at RT. After 30 min, solid 2,2,3,3,3-pentafluoropropyl 4-methylbenzenesulfonate (5 g, 16.4 mmol) was added into the reaction mixture. The mixture was stirred and heated at 100° C. for 7 h. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water (3×) and brine, and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane afforded 4-(2,2,3,3,3-pentafluoropropoxy)benzaldehyde (1.26 g).
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])=[O:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]([F:31])([F:32])[F:33])[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: CP(C)(=O)CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(C)(=O)CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
1-[(dimethylphosphoryl)methyl]piperazine (3.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane. Triethylamine (4.04 g, 11 eq.) was carefully added. The reaction solution temperature rose to 30° C. before cooling down to room temperature after 5 minutes. After 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (60 weight %, 3.88 g, 7.9 mmol, 2.2 eq) was added in one portion, the reaction mixture was stirred at room temperature for 30 minutes under N2 protection. After the volatile components were evaporated, the reaction mixture was purified via column chromatography to give title compound as light yellow solid (740 mg). MS (LC/MS): 378.3 [M−]. 31P-NMR (300 MHz, CDCl3): 42.8.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:16]=1[NH:25][C:26]([CH:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:27].O[NH:39][C:40](=[NH:53])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]>C1COCC1>[CH2:41]([C:40]1[N:39]=[C:29]([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]([NH:25][C:16]2[C:17]([O:23][CH3:24])=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:15]=2[O:14][CH3:13])=[O:27])[O:30][N:53]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Reactant: CCCCCCCCCCCCC(=N)NO
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1noc(C(C(=O)Nc2c(OC)cc(OC)cc2OC)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
Carbonyl dimidazole (0.28 g, 1.71 mmol) was added to a solution of α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]-benzene acetic acid (0.56 g, 1.63 mmol) in dry THF (20 mL), and the resulting mixture was stirred at room temperature for 1 hour, then N-hydroxy-tridecane imidamide (0.37 g, 1.63 mmol) was added, and the mixture stirred for 1.5 hours, concentrated in vacuo, dissolved in glacial acetic acid, and refluxed for 1.5 hours. The solution was concentrated and azeotroped with benzene (2×25 mL), dissolved in ethyl acetate, and washed with NaHCO3, water, brine, dried with MgSO4, and recrystallized from ethanol/water to yield a white solid (0.093 g, 11%). %(found): C, 69.25; H, 8.08; N, 7.68. ##STR14##
Reaction SMILES: [CH2:1](OC(C)(C)CCCC(C)CC=CC(=O)C)C.[CH2:18]([O:20][C:21]([CH3:38])([CH3:37])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:36])[CH2:26][CH:27]=[CH:28][C:29]([CH3:35])=[CH:30][C:31]([O:33][CH3:34])=[O:32])[CH3:19].C(CP(=O)(OCC)OCC)(OCC)=O>>[CH2:18]([O:20][C:21]([CH3:37])([CH3:38])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:36])[CH2:26][CH:27]=[CH:28][C:29]([CH3:35])=[CH:30][C:31]([O:33][CH2:34][CH3:1])=[O:32])[CH3:19]
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC
Reactant: CCOC(C)(C)CCCC(C)CC=CC(C)=O
Agent: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)C=C(C)C=CCC(C)CCCC(C)(C)OCC

Procedure:
Following the process of Example 13, 10-ethoxy-6,10-dimethylundec-3-en-2-one is converted into methyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate. Reaction of 10-ethoxy-6,10-dimethylundec-3-en-2-one with the carbanion of diethyl carboethoxymethylphosphonate yields ethyl 11-ethoxy-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(F)cc1Nc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-fluoro-N-methoxy-N-methyl-2-phenylamino-benzamide (9.35 g, 34.1 mmol) in THF (170 mL) was added ethylmagnesium bromide (1M solution in THF) (136 mL, 136 mmol) dropwise at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for 4 hr. At this time, only 50% of the starting material was consumed. The reaction mixture was cooled again to 0° C. To push the reaction to completion, a 3M solution of ethylmagnesium bromide in diethyl ether (50 mL, 150 mmol) was added slowly to the cooled reaction mixture. The reaction was quenched with an aqueous solution of 1N HCl at 0° C. and was extracted with ethyl acetate. The combined organic layer was washed with water and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography (100% hexanes ramped to 6% ethyl acetate in hexanes) to give 1-(4-fluoro-2-phenylamino-phenyl)-propan-1-one.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.Br[CH2:21][CH2:22][NH:23][S:24](=[O:36])([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1)=[O:25].[OH-].[K+]>CO>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:21][CH2:22][NH:23][S:24](=[O:36])([C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:30][CH:31]=3)=[O:25])[CH:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCBr)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCNS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
A mixture of 1.41 g (0.005 mole) of 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride, 2.0 g (0.00625 mole) of N1 -(2-bromoethyl)-N4 -acetylsulfanilamide, 25 ml of methanol, and 6.0 ml of an aqueous solution containing 0.013 mole of potassium hydroxide is heated at reflux for 1.5 hr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)[CH2:9][C:10]#[N:11])=[N:6][CH:7]=1.[NH2:30][OH:31]>CCO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[C:14]([F:22])[CH:13]=2)([NH:23][S@:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[O:25])[CH2:9]/[C:10](/[NH2:11])=[N:30]/[OH:31])=[N:6][CH:7]=1
Reactant: NO
Reactant: CC(C)(C)[S@](=O)N[C@](CC#N)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N[C@](C/C(N)=N/O)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 70 °C

Procedure:
(S)-N-((R)-1-(5-chloropyridin-2-yl)-2-cyano-1-(3-fluoro-5-(trifluoromethyl) phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.030 g, 0.067 mmol) was dissolved in EtOH (1 mL) in a 2 dram vial. NH2OH (1 mL, 50% solution in water) was added and the sealed screw capped vial was heated to 70° C. for 3 h. The cooled solution was diluted with DCM (10 mL) and transferred to a separation funnel. The organic layer was separated and the aqueous portion was washed further with DCM (5 mL). The combined organic portions were dried, decanted and concentrated yielding (R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-N′-hydroxy-3-((S)-2-methylpropan-2-ylsulfinamido)propanamidine as a tan oil (0.032 mg, quantitative yield). LCMS: 1.50 min [M+1] 481.1 (2 min gradient, MeOH/H2O 0.1% TFA). The crude oil was dissolved in dry DCM (1 mL), cooled to 0° C. and TEA (25pL) was added followed by acetic anhydride (11 μL). The reaction mixture was allowed to reach room temperature with stirring over 18 h. The solution was diluted with DCM (10 mL), transferred to a separation funnel, washed with sat. NaCl (10 mL), dried, decanted and concentrated yielding a white solid. LCMS: 1.87 min [M+1] 523.1 (2 min gradient, MeOH/H2O 0.1% TFA). The intermediate N-((R,Z)-3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(hydroxyimino)-3-((S)-2-methylpropan-2-ylsulfinamido)propyl)acetamide was redissolved in anhydrous THF (2 mL) and anhydrous Cs2CO3 was added (0.063 g). The solution was heated to 105° C. for 3 h whereupon the solvent evaporated leaving a pale brown solid which was dissolved in MeOH (1 mL) and purified by prep HPLC (YMC ODSA30×100 mm, 0-100% over 10 min, MeOH/H2O/0.1% TFA) yielding (S)-N-((R)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-2-methylpropane-2-sulfinamide as a colorless oil (0.015 g, 44% yield over 3 steps). LCMS: 1.96 min [M+1] 505.1 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.80 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 96%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:12](=[O:20])[CH2:11][CH:10]2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH3:33][NH:34][CH3:35]>CN(C)C=O>[CH3:33][N:34]([CH2:21][CH:10]1[CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:20])[CH2:11]1)[CH3:35]
Reactant: CNC
Reactant: COc1cccc(C2C(COS(=O)(=O)c3ccc(C)cc3)CC(=O)N2c2ccccc2)c1
Solvent: CN(C)C=O
Product: COc1cccc(C2C(CN(C)C)CC(=O)N2c2ccccc2)c1
Reaction time: 3 h

Procedure:
To. 22.0 gm. of 5-(3-methoxyphenyl)-1-phenyl-4-(p-toluenesulfonyloxymethyl)pyrrolidin-2-one in 150 ml. of dimethylformamide was added 21 ml. of 40% aqueous dimethylamine, the solution refluxed for 3 hours and then 21 ml. more of 40% aqueous dimethylamine added and reflux continued for an additional 3 hours. After cooling the reaction was decanted into ice water and acidified. Extraction with ether followed by basification of the aqueous phase with potassium carbonate yielded a semi-solid which was extracted with chloroform, dried (Na2SO4), filtered and concentrated in vacuo to a solid. Recrystallization from acetonitrile provided 7.0 gm. of beige crystals, m.p. 88°-92°.
Reaction SMILES: [Na].CO.[CH2:4]([NH:6][S:7]([C:10]([F:34])([F:33])[C:11]([F:32])([F:31])[C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[CH3:5].[N:35]1[C:42](Cl)=[N:41][C:39](Cl)=[N:38][C:36]=1[Cl:37]>CC(C)=O>[Cl:37][C:36]1[N:35]=[C:42]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:34])([F:33])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:41]=[C:39]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:33])([F:34])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:38]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na]
Solvent: CC(C)=O
Solvent: CO
Product: CCN(c1nc(Cl)nc(N(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)n1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Metallic sodium (4.08 g, 177 mmols) was reacted with methanol (150 mls). N-Ethyl perfluorooctyl sulphonamide (93.28 g, 177 mmols) was added, and the resulting solution was stirred for 30 minutes. The methanol was removed at the pump (a vacuum pump was required to remove the final traces of solvent). The resulting sticky solid was dissolved in acetone (300 mls) and cooled to −65° C. under argon. Recrystalised cyanuric chloride (16.33 g, 88.5 mmols) dissolved in acetone (100 mls) was added to the reaction mixture dropwise such that the temperature did not rise above −50° C. (˜1 hour). After the addition, the reaction mixture was allowed to slowly warm to room temperature (1 hour) and then stirred for a further 3 hours. The precipated solid was removed by filtration and dried under vacuum. Purification by soxhlet extraction with acetone afforded 61 g (56.9%) of a fine white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:49])([F:48])[C@:30]([C:33]3[CH:38]=[C:37](B4OCC(C)(C)CO4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[C:53]1[N:54]=[CH:55][N:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH:57]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:51])([CH3:50])[C:29]([F:48])([F:49])[C@:30]([C:33]3[CH:38]=[C:37]([C:53]4[N:54]=[CH:55][N:56]([C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=5)[CH:57]=4)[CH:36]=[CH:35][C:34]=3[F:47])([CH3:32])[N:31]=2)([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(B4OCC(C)(C)CO4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Brc1cn(-c2ccccn2)cn1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cn(-c5ccccn5)cn4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 25 %

Procedure:
Reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (intermediate B10.1) (300 mg, 380 μmol) with 2-(4-bromo-1H-imidazol-1-yl)pyridine [CAS 556775-77-0; J. Med. Chem. 47(19), 4645 (2004)) (111 mg, 494 μmol) yielded the [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-6,6-difluoro-5-[2-fluoro-5-(1-pyridin-2-yl-1H-imidazol-4-yl)-phenyl]-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (71 mg, 25% yield) as a light red foam. MS (ISP): m/z=732.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(C#N)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.[CH3:24][NH:25][CH3:26]>C1COCC1.O>[CH3:24][N:25]([CH3:26])[C:9](=[O:10])[C:11]1[C:6]([C:7]([C:12]2[N:13]=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([O:18][CH3:19])[N:17]=2)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: CNC
Reactant: COc1cc(OC)nc(C2(C#N)OC(=O)c3c(Cl)cccc32)n1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(=O)c2cccc(Cl)c2C(=O)N(C)C)n1
Reaction time: 0.25 h

Procedure:
1.0 g of 7-chloro-3-cyano-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide is dissolved in 15 ml of THF. 0.7 ml of a 40% aqueous dimethylamine solution is then added via syringe whereupon the solution darkens. Stirring is continued at R.T. for 15 minutes and the mixture diluted with water and partitioned between ethyl acetate and water. The organic phase is separated, washed with 2N H2SO4, then brine, dried and concentrated. The residue is purified on silica gel, eluant 200 ml of 50% ethyl acetate/hexane then 100% ethyl acetate. Fractions 12 to 15 yielded the title compound, m.p. 141°-142° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[N:18]1([C:2]2[N:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[N:5]=[C:4]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:3]=2[N+:15]([O-:17])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1c(Cl)nc(C2CC2)nc1NC1CC1
Product: O=[N+]([O-])c1c(NC2CC2)nc(C2CC2)nc1N1CCCCCC1

Procedure:
6-(1-azepanyl)-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 197 was synthesized as described in 7.1 using 6-chloro-N,2-dicyclopropyl-5-nitro-4-pyrimidinamine 44 and azepane as starting material.