Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:4][CH:3]=1.C(C1C=CC(NC2C=CC=CC=2CN2C(C)(C)C(=O)N(C3C=CC(C#N)=C(C(F)(F)F)C=3)C2=O)=CC=1C(F)(F)F)#N>>[CH3:17][C:16]1([CH3:18])[C:15](=[O:19])[N:14]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)[C:13](=[O:32])[N:12]1[CH2:11][C:10]1[CH:33]=[CH:34][CH:35]=[CH:36][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccc(F)cc1
Agent: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccc(C#N)c(C(F)(F)F)c1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccccc1Nc1ccccc1

Procedure:
The compounds of example 2, 4-{3-[2-(4-fluorophenylamino)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 496.15 (C26H20F4N4O2); retention time Rt=2.25 min. [B]; MS (ESI): 497.28 (MH+), and of examples 3, 4-{3-[2-(4-cyano-3-trifluoromethylphenylamino)benzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 571.14 (C28H19F6N5O2); retention time Rt=2.17 min. [B]; MS (ESI): 572.38 (MH+),
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][C:14]3[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl.N>O1CCOCC1.CO>[CH3:12][C:8]1[C:7]([O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([O:30][C:29]([F:28])([F:38])[F:39])[CH:32]=1)=[N:3][CH:4]=[CH:5]2
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Cl)nccc23)n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Nc4cccc(OC(F)(F)F)c4)nccc23)n1
Temperature: 170 °C

Procedure:
4-(2-(1-Chloro-6-methylisoquinolin-5-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.150 g, 0.40 mmol) was suspended in dioxane (1.00 mL) to which mixture was added 3-(trifluoromethoxy)aniline (0.12 ml, 0.79 mmol). 4N HCl in dioxane (1.00 mL) was added and the mixture was stirred. The vessel was sealed and heated to 170° C. in microwave for 15 minutes. The reaction mixture was treated with 2M ammonia in methanol and concentrated directly onto silica gel. The material was chromatographed eluting with a gradient of EtOAc/hexanes (15-100%) followed by trituration of the pure material in EtOAc to afforded 6-methyl-5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)-N-(3-(trifluoromethoxy)phenyl)isoquinolin-1-amine. MS (M+H)+ 519.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:28]([CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CNc1ccccc1
Product: COc1ccc(-c2nc(CN(C)c3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline was reacted with N-methylaniline to give 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(N-methyl-N-phenylaminomethyl)quinazoline. This compound was recrystallized from ethanol. Colorless needles, mp. 141°-143° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:21])[CH2:7][N:8]([S:10]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH3:20])(=[O:12])=[O:11])[CH3:9])(=O)C.C(N(CC)CC)C.O>CO>[CH3:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[S:10]([N:8]([CH2:7][C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:21])[CH2:5][OH:4])[CH3:9])(=[O:11])=[O:12]
Reactant: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1cc(C)ccc1C)c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(C)c(S(=O)(=O)N(C)CC(O)(CO)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of 3.50 g of 1-acetoxy-3-[N-(2,5-dimethylphenylsulfonyl)-N-methylamino]-2-phenyl-2-propanol prepared in the above-described way, 3 ml of triethylamine, 3 ml of water and 6 ml of methanol was stirred at room temperature for 4 hours. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: benzene-ethyl acetate (4:1)) to obtain 2.80 g of the titled compound.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([NH:17][C:18]([NH:20][C@@:21]([C:36]1[CH:41]=[C:40]([O:42][C:43]([F:48])([F:47])[CH:44]([F:46])[F:45])[CH:39]=[C:38]([F:49])[CH:37]=1)([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])[C@@H:11]([OH:16])[C:12]([F:15])([F:14])[F:13])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:49][C:38]1[CH:37]=[C:36]([C@:21]([NH:20][C:18]([NH:17][C@@H:10]([C@@H:11]([OH:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][OH:8])=[O:19])([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:41]=[C:40]([O:42][C:43]([F:48])([F:47])[CH:44]([F:46])[F:45])[CH:39]=1
Reactant: O=C(N[C@H](COCc1ccccc1)[C@@H](O)C(F)(F)F)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)[C@@H](O)C(F)(F)F)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1

Procedure:
To a solution of 1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (Example 236, 17 mg, 0.024 mmol) in THF (1 mL) was added 20% Pd(OH)2/C (8 mg) and the slurry was subjected to balloon hydrogenation for 18 h. The reaction mixture was filtered and the filtrate was concentrated and purified by preparative HPLC (Shimadzu-YMC-ODS-A 5μ column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm) to yield 1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-((2R,3R)-4,4,4-trifluoro-1,3-dihydroxybutan-2-yl)urea (Example 237) eluting at a retention time of 11.54 min as a clear oil (11 mg, yield 78%). LCMS: RT=1.983 min [M+H] 611.26 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA, 5 mL/min, monitoring at 220 nm); HPLC: RT=4.081 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.20 ppm, 1H, s; 7.16 ppm, 5H, m; 6.99 ppm, 2H, m; 6.91 ppm, 3H, m; 6.70 ppm, 2H, d, J=7.47 Hz; 5.87 ppm, 1H, m; 5.38 ppm, 1H, d, J=7.47 Hz; 5.35 ppm, 1H, s; 4.28 ppm, 1H, d, J=5.71 Hz; 4.11 ppm, 2H, m; 3.94 ppm, 2H, d, J=7.91 Hz; 3.82 ppm, 1H, m; 3.73 ppm, 1H, m; 3.67 ppm, 1H, d, J=8.35 Hz.
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:24])([F:23])[C:9]1[C:10]([S:15]([NH:18][C:19](=[O:22])OC)(=[O:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:25][C:26]1[CH2:30][C:29]([CH3:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:28][N:27]=1>N1C=CC=CC=1>[F:23][C:8]([F:7])([F:24])[C:9]1[C:10]([S:15]([NH:18][C:19]([N:28]2[C:29]([CH3:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:30][C:26]([CH3:25])=[N:27]2)=[O:22])(=[O:16])=[O:17])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Reactant: CC1=NNC(C)(c2ccccc2)C1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1=NN(C(=O)NS(=O)(=O)c2ncccc2C(F)(F)F)C(C)(c2ccccc2)C1
Reaction time: 1 h
Yield: 86 %

Procedure:
A dry dioxane (10 ml) solution containing methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate (0.43 g, 1.5 mmol), 3,5-dimethyl-5-phenyl-2-pyrazoline (0.52 g, 3.0 mmol) and pyridine (0.45 g) was refluxed under heating and stirring for one hour. After cooling the mixture, the solvent was distilled off under reduced pressure, and the residue was stirred together with ethyl ether. Precipitated crystals were collected by filtration and then thoroughly washed with ethyl ether, and the crystals were suspended in 20 ml of water. Then, the pH was adjusted to a level of from 1 to 2 with concentrated hydrochloric acid, and the suspension was stirred at room temperature for 5 minutes. Crystals were collected by filtration, thoroughly washed with water and then with ethyl ether and dried to obtain 0.55 g of desired 1-(3-trifluoromethylpyridine-2-sulfonylcarbamoyl)-3,5-dimethyl-5-phenyl-2-pyrazoline. Melting point: 152°-153° C.
Reaction SMILES: [C:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=1)([CH:23]([CH3:25])[CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)#[N:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH:23]([CH3:25])[CH3:24])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: COc1ccc(C(C#N)(CCCN2CCN(CCOc3ccc(F)cc3)CC2)C(C)C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccc(F)cc2)CC1)c1ccc(O)cc1

Procedure:
1-[4-Cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine 85 mg obtained in Example 11 was dissolved in dichloromethane 3 ml, and 1M-boron tribromide (dichloromethane solution, 0.5 ml) was added dropwise thereto under ice-cooling. After haeting the mixture under reflux for 5 hours, it was cooled to room temperature and basified with aqueous saturated sodium bicarbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried over sodium sulfate anhydride, and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound 30 mg, 36% was obtained as a colorless oil.
Reaction SMILES: [CH2:1]1[CH:11]2[CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@@:22]([NH:26]C(=O)OC(C)(C)C)([CH3:25])[CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)[C:10]=12.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]1[CH:11]2[CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[C@@:22]([NH2:26])([CH3:25])[CH2:23][CH3:24])=[CH:15][CH:14]=3)[C:10]=12
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc3c2C2CC2CO3)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2CC2CO3)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
In a 50 mL round-bottomed flask tert-butyl N-[(1R)-1-[[6-(1,1a,2,7b-tetrahydrocyclopropa[c]chromen-7-yloxy)-3-pyridyl]carbamoyl]-1-methyl-propyl]carbamate (Intermediate 227, 74 mg, 0.139 mmol) was dissolved in Dichloromethane (3 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. The sample was charged on a 2 g SCX cartridge. It was then flushed with 36 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated in vacuo affording the title compound (46.2 mg) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:12]=1[N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([S:25]([Cl:24])(=[O:27])=[O:26])[CH:3]=[C:2]([F:1])[C:11]1=2)#[N:15]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cccc(F)c21
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)cc(F)c21
Reaction time: 1.5 h
Yield: 21.1 %

Procedure:
To a vial charged with 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.445 g, 1.381 mmol) was added DCM (5.52 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.367 ml, 5.52 mmol), faster than dropwise. After 90 mins of stirring LC-MS of the resulting yellow/brown suspension indicated two peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material. The mixture was added to ice, diluted with water and extracted with EtOAc (2×). The combined organics were dried under reduced pressure and purified with a 40 HP spherical silica column (15 m spherical, Interchim) ramping EtOAc in heptane (0-35%, 10% DCM throughout) yielding near complete separation of isomers. NMR analysis of the first eluted peak confirmed the desired regiochemistry 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol, 21.17% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-4.02 (m, 2 H) 4.37 (br. s., 2 H) 6.97 (dd, J=9.10, 1.56 Hz, 1 H) 7.20 (d, J=8.61 Hz, 1 H) 7.64 (dd, J=9.10, 7.34 Hz, 1 H) 7.77 (dd, J=8.61, 2.15 Hz, 1 H) 7.97 (d, J=1.76 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: OO.[OH:3][C:4]([CH3:39])([CH3:38])[CH2:5][C@@:6]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:31])([CH3:30])[C:28]#[N:29])=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1.C([O-])([O-])=[O:41].[K+].[K+].[O-]S([O-])(=S)=O.[Na+].[Na+]>>[OH:3][C:4]([CH3:38])([CH3:39])[CH2:5][C@@:6]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([CH3:30])([CH3:31])[C:28]([NH2:29])=[O:41])=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](c1ccc(-c2ccc(C(C)(C)C#N)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [K+]
Product: C[C@@H](c1ccc(-c2ccc(C(C)(C)C(N)=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydrogen peroxide (35% in water, 0.1 mL) was added to a mixture of 2-[5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridin-2-yl]-2-methyl-propionitrile (0.21 g; for preparation see Example 194) and K2CO3 (0.03 g) in ddimethyl sulfoxide (2 mL) at room temperature. After stirring the mixture for 3 h at room temperature, another portion of hydrogen peroxide (35% in water, 0.1 mL) and K2CO3 (0.03 g) were added. The mixture was further stirred at room temperature for 1 h and at 40° C. overnight. After cooling to room temperature, little aqueous Na2S2O3 solution was added and then the mixture was concentrated. The residue was purified by HPLC on reversed phase (methanol/water/ammonia) to furnish the title compound. Yield: 0.03 g (14% of theory); Mass spectrum (ESI+): m/z=516 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[C:5]1[CH3:30].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[Br:1][C:7]1[N:6]=[C:5]([CH3:30])[N:4]([CH3:3])[C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:29])(=[O:28])[NH:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:21]=2)[N:10]=1
Reactant: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3C)n2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCNS(=O)(=O)c1ccc(Nc2nccc(-c3c(Br)nc(C)n3C)n2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A 1M solution of bromine in acetic acid (8.49 ml, 8.49 mmol) was added to a solution of 4(1,2-dimethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)sulphamoyl]anilino}pyrimidine (Example 35 in WO 02/20512; 3.1g, 7.71mmol) in acetic acid (24 ml) heated at 70° C. under nitrogen. The mixture was stirred at 70° C. for 1 hour, allowed to cool, diluted with water and carefully neutralised with saturated aqueous sodium hydrogen carbonate solution. The aqueous solution was extracted with EtOAc, the extracts combined, dried and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (95:5 increasing in polarity to 90:10) to give the title compound (1 g, 24%). NMR: 2.38 (s, 3H), 2.87 (s, 2H), 2.51 (q, 2H), 3.16 (s, 3H), 3.52 (s, 3H), 7.49 (s, 1H), 7.70 (d, 2H), 7.88 (d, 2H), 8.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:48][CH:49]1[CH2:53][CH2:52][NH:51][CH2:50]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[OH:48][CH:49]1[CH2:53][CH2:52][N:51]([C:21]([C:19]2[S:20][C:13]3[C:14](=[N:15][CH:16]=[CH:17][C:12]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:18]=2)=[O:23])[CH2:50]1
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: OC1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(O)C5)sc34)ccc2[nH]1
Yield: 76.4 %

Procedure:
To a solution of 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid (0.10 g, 0.31 mmol), HATU (0.17 g, 0.46 mmol) and DMAP (0.040 g, 0.31 mmol) in DMF (3 mL) was added racemic 3-hydroxy-pyrrolidine (0.040 g, 0.46 mmol). After 3 h the reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and EtOAC (10 mL). The aquenched layer was further extracted with EtOAC (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 85:15) afforded the title compound as a yellow solid (0.093 g, 76%). MS: 393 (MH+); HPLC Rf: 3.41; HPLC purity: 87%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])[CH3:2].[CH3:16]C(O)C>>[CH3:2][CH:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:11](=[O:12])[O:10][CH2:9]2)=[O:5])[CH3:16]
Reactant: CC(C)O
Reactant: CCOC(=O)c1ccc2c(c1)COC2=O
Product: CC(C)OC(=O)c1ccc2c(c1)COC2=O
Temperature: 0 °C

Procedure:
Method B): 5-Ethoxycarbonylphthalid (52 g, 0.25 mole) is suspended in 2-propanol (1000 mL). Ti(iPro)4 (38 g, 0.14 mole) is added and the mixture is refluxed for 3 hours. The reaction mixture is cooled to 0° C. and the crystals are filtered off and washed with cold 2-propanol (70 mL). Yield: 47 g, 85%. DSC onset 144° C.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[C:14]([CH2:19][CH:20]1[C:25](=[O:26])[CH:24]=[C:23]([CH3:27])[CH2:22][CH2:21]1)(OCC)=[O:15].O1C2C=CCCC2CC1=O>C1(C)C=CC=CC=1>[CH3:27][C:23]1[CH2:22][CH2:21][C@H:20]2[CH2:19][C:14](=[O:15])[O:26][C@H:25]2[CH:24]=1
Reactant: CCOC(=O)CC1CCC(C)=CC1=O
Agent: CC(C)[O-]
Agent: O=C1CC2CCC=CC2O1
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CC1=C[C@@H]2OC(=O)C[C@@H]2CC1
Yield: 73 %

Procedure:
The reaction of 18.73 g (91.7 mmoles) of aluminum isopropoxide in 150 ml of toluene with 3.0 g (15.3 mmoles) of 6-(carbethoxymethyl)-3-methyl-2-cyclohexen-l-one was conducted in a similar manner to the synthesis of 3a,4,5,7a-tetrahydro-2(3H)-benzofuranone described in Example I. The crude material was purified by Kugelrohr distillation (bp 55°-80° C./0.0l mm Hg) to yield 1.7 g (74%) of cis 6-methyl-3a,4,5,7a-tetrahydro-2(3H)-benzofuranone, as confirmed by NMR and IR data.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][CH2:30][O:31][C:32]1[C:41]([CH3:42])=[C:40]2[C:35]([CH:36]=[CH:37][C:38]([CH:43]=O)=[N:39]2)=[CH:34][CH:33]=1>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:43]/[C:38]2[CH:37]=[CH:36][C:35]3[C:40](=[C:41]([CH3:42])[C:32]([O:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:33][CH:34]=3)[N:39]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCOc1ccc2ccc(C=O)nc2c1C
Solvent: CCO
Product: COCCOc1ccc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc2c1C

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (98.0 mg, 0.261 mmol) and 7-(2-methoxyethoxy)-8-methylquinoline-2-carbaldehyde (64 mg, 0.261 mmol) were stirred in ethanol at ambient temperature for 24 hours. The reaction was concentrated and used as is in the next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16].O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([OH:17])[CH3:16]
Reactant: COc1ccccc1C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C(C)O
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (1.52 g) was suspended in tetrahydrofuran (100 ml), 2′-methoxyacetophenone (2.76 ml) was added under ice-cooling, and the mixture was stirred for 30 min. To the reaction mixture were successively added water (1.5 ml), 15% aqueous sodium hydroxide solution (1.5 ml) and water (4.5 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (3.05 g).
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[N:10]([CH2:11][CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([Cl:17])=[CH:16][C:8]=2[N:7]=1)([OH:5])[CH3:4].[F:19][C:20]([F:24])([F:23])[CH2:21][SH:22].C[O-].[Na+]>CO>[Cl:17][C:15]1[C:14]([Cl:18])=[CH:13][C:9]2[N:10]([CH2:11][CH3:12])[C:6]([C:3]([OH:5])([CH3:4])[CH2:2][S:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[N:7][C:8]=2[CH:16]=1
Reactant: FC(F)(F)CS
Reactant: CCn1c(C(C)(O)CCl)nc2cc(Cl)c(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(C(C)(O)CSCC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-chloro-2-(5,6-dichloro-1-ethyl-1H-benzoimidazol-2-yl)-propan-2-ol (249 mg) in methanol (5 mL) at room temperature was added a solution of 2,2,2-trifluoroethanethiol (109 mg) and sodium methoxide (0.222 mls of 25 wt % in MeOH). The resulting mixture was then stirred at room temperature overnight. The reaction mixture was concentrated. The crude product was purified by flash chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.