Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:27])([F:26])[C:8]([CH2:14][CH:15]1[CH:20]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:19]2[CH2:25][CH:16]1[CH2:17][CH2:18]2)([OH:13])[C:9]([F:12])([F:11])[F:10].[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>O1CCCC1>[C:28]([O:13][C:8]([CH2:14][CH:15]1[CH:20]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:19]2[CH2:25][CH:16]1[CH2:17][CH2:18]2)([C:9]([F:11])([F:10])[F:12])[C:7]([F:26])([F:27])[F:6])(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: CC(C)(O)C1C2CCC(C2)C1CC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC(CC1C2CCC(C2)C1C(C)(C)O)(C(F)(F)F)C(F)(F)F
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 30.1 %

Procedure:
To a flame-dried, nitrogen-purged 250 mL 3-neck roundbottom flask with 50 mL pressure-equalizing addition funnel and magnetic stirbar was charged 141 mL n-butyl lithium (65 mmol, 2 equiv., 1.6 M in hexanes). A degassed solution of 1,1,1,3,3,3-hexafluoro-2-((3-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-2-yl)methyl)propan-2-ol (VII) (˜33 mmol, 1 eq.) in 50 mL anhydrous tetrahydrofuran was charged to the addition funnel was added to the reaction mixture dropwise at 0° C. over 30 minutes. The reaction mixture was warmed for 15 minutes on an oil bath at 70° C. to ensure the reaction was complete. The reaction vessel was cooled to 0° C. and 3.75 g methacryloyl chloride (36 mmol, 1.1 eq.) was added dropwise and allowed to stir for 15 minutes. The addition funnel was replaced with a reflux condenser and the reaction heated to reflux for 20 hours. After the reaction was complete, it was cooled to 0° C. and quenched with dilute HCl solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed sequentially with aqueous sodium bicarbonate, water, and brine and then dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. The crude product mixture was purified via silica gel column chromatography (20:1 hexane:ethyl acetate eluent) to afford 4.0 g (30%) of 1,1,1,3,3,3-hexafluoro-2-((3-(2-hydroxypropan-2-yl)bicyclo[2.2.1]heptan-2-yl)methyl)propan-2-yl methacrylate (VIII) as a colorless liquid (˜1.35:1 isomer ratio).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][NH:6][C:7]([C:9]1([CH2:22][CH2:23][CH2:24][CH2:25][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:8]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCc1ccc(F)c(F)c1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)c(F)c1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-3,4-difluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23](Cl)=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])C.[BH4-].[Na+].[NH:41]1[CH2:46]CCC[CH2:42]1>C1COCC1.CN(C1C=CN=CC=1)C>[Si:1]([O:8][CH2:9][C:10]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:41]([CH3:46])[CH:42]1[CH2:36][CH2:35][NH:34][CH2:37][CH2:38]1)=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.25 g (2.7 mmol) of chloroformate 6-1 in THF was added 1.2 mL (8.1 mmol) of triethylamine, 590 mg (3.0 mmol) of amine 7-1 (Supplier: High Force Research Ltd.), and a catalytic amount of DMAP. After stirring overnight at room temperature, the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, 10% KHSO4, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide a colorless oil. This material (1.32 g, 2.1 mmol) was dissolved in anhydrous THF and N2 was bubbled through the solution for 5 minutes. To this mixture was then added 320 mg (8.4 mmol) of NaBH4, 835 μL (8.4 mmol) of piperidine, and 122 mg (0.10 mmol) of tetrakistriphenylphosphine palladium(0). After stirring for 2 h at room temperature, the reaction was quenched with saturated NaHCO3, poured into EtOAc and the layers were separated. The organic phase was washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 7-2 as an off-white solid. Data for 7-2: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.35 (s, 1H), 4.8 (m, 1H), 4.7-4.6 (m, 2H), 4.45 (m, 1H), 3.6 (m, 1H), 3.1 (m, 2H) 2.75 (s, 3H), 2.7-2.6 (m, 2H), 2.05 (bs, 1H), 1.8-1.6 (m, 4H), 0.8 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H) ppm. HRMS (ES) calc'd M+H for C30H41F2N3O2Si: 542.3009. Found: 542.2999.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[CH3:12]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CN(C)CCN
Product: CN(C)CCN=Cc1cc2ccccc2[nH]1
Yield: 96.1 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.200 g (1.378 mmol) of 1H-indole-2-carbaldehyde instead of pyrrole-2-carbaldehyde and use 0.158 mL (1.447 mmol) of the N1,N1-dimethylethane-1,2-diamine to give 0.285 g (96%) of N1-((1H-indol-2-yl)methylene)-N2,N2-dimethylethane-1,2-diamine as an off-white solid, which is analytically pure by GC-MS and 1H-NMR: 1H NMR (400 MHz, CDCl3) δ 9.11 (s, br, 1H), 8.19 (s, br, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.00 (t, J=7.4 Hz, 1H), 6.65 (s, br, 1H), 3.64 (t, J=6.3 Hz, 2H), 2.53 (t, J=6.7 Hz, 2H), 2.22 (s, 6H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[I-].[K+].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1>C(#N)C>[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][N:46]([CH2:6][CH2:7][CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][S:19]([NH:22][CH3:23])(=[O:21])=[O:20])[CH:16]=4)[NH:11][CH:10]=3)[CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1
Reactant: COc1cncnc1N1CCNCC1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)CC3)c2c1
Yield: 57.6 %

Procedure:
To a solution of crude 3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl methanesulfonate (18.3 mmol, 1.0 equiv.) in 225 mL of anhydrous acetonitrile was added 3.03 g (18.3 mmol, 1.0 equiv.) of potassium iodide, 3.81 mL (21.9 mmol, 1.2 equiv.) of N,N-diisopropylethylamine and 3.89 g (20.1 mmol, 1.1 equiv.) of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for sixteen hours. The reaction mixture was concentrated in vacuo and the residue was taken up in 500 mL of chloroform. The organic layer was washed with 100 mL portions of 10% potassium carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield an oil. The oil was purified by chromatography on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide followed by chromatography on silica gel using 20% methanol in ethyl acetate to obtain 4.83 g (58%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine. The hydrochloride salt was prepared by addition of 3N ethanolic HCl. Two recrystallizations from hot methanol gave 4.05 g (68%) of 4-(5-methoxy-4-pyrimidinyl)-1-[3-[5-[[(methylamino)sulfonyl]methyl]-1H-indol-3-yl]propyl]piperazine hydrochloride, m.p. 170° C. (d). Elemental analysis calculated for C22H30N6O3S/3 HCl: C, 46.52; H, 5.86; N, 14.80; found: C, 46.14; H, 6.22; N, 14.51.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].OCC(OC[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: O=C(CO)OCc1ccccc1
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Product: O=C(COS(=O)(=O)C(F)(F)F)OCc1ccccc1

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with HO-CH2COOBn
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16](O)=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.COC1C(OC)=CC2C(=O)[N:27]3N=C(C(N)=O)C=C3NC=2C=1>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[C:12]2[NH:11][C:10]3=[CH:13][C:14]([C:16]([NH2:27])=[O:17])=[N:15][N:9]3[C:8](=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(=O)n3nc(C(=O)O)cc3[nH]c12
Reactant: COc1cc2[nH]c3cc(C(N)=O)nn3c(=O)c2cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(=O)n3nc(C(N)=O)cc3[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,9-dihydro-5-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (6.6 g; 0.025 mole) and phosphorous oxychloride (100 ml) is stirred at room temperature overnight. The solid is filtered off, washed with ether, dried and treated with cold (0° C.) ammonium hydroxide solution (58%; 50 ml). After standing overnight at room temperature the product is filtered off, dried and used in the next step without further purification. Yield 5.06 g; mp 265°-270° C. By the same procedure, starting with the corresponding 6,7-dimethoxy compound, the product obtained is 4,9-dihydro-6,7-dimethoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:13][C:14]2([NH:17]C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[CH2:10][CH2:11][OH:12])=[CH:4][C:3]=1[C:25]([NH:27][CH2:28][C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2)=[O:26].Cl.N>CO.O1CCOCC1>[NH2:17][C:14]1([CH2:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:4]=2)[C:25]([NH:27][CH2:28][C:29]23[CH2:30][CH:31]4[CH2:32][CH:33]([CH2:34][CH:35]([CH2:37]4)[CH2:36]2)[CH2:38]3)=[O:26])[CH2:10][CH2:11][OH:12])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: NC1(CN(CCO)Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
[1-[[[[4-Chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-methyl](2-hydroxyethyl)amino]methyl]cyclopropyl]-carbamic acid, 1,1-dimethylethyl ester (Example 71d, 0.302 g) was dissolved in methanol (10 ml) and 4N HCl in dioxane (10 ml) was added. The mixture was stirred for 14 h at room temperature, then poured into 25% aqueous ammonia solution and concentrated under reduced pressure to give the free base. This was purified by column chromatography over silica (eluting with 19:1:0.1 dichloromethane/methanol/ammonia) to afford the title compound as an oil (0.230 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2O.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClC(Cl)C>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Oc1ncnc2ccc(I)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: Clc1ncnc2ccc(I)cc12
Temperature: 90 °C
Yield: 71.4 %

Procedure:
To a cooled (0° C.) suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138 mL, 791 mmol) in dichloroethane (600 mL) was added POCl3 (44.25 mL, 475 mmol). After heating to 90° C. for 16 hours, the reaction mixture was cooled to room temperature and the crystals (73.8 g) collected by filtration. The filtrate was concentrated under reduced pressure and azeotroped twice with toluene. The solids (8.3 g) were triturated with isopropanol (450 mL) and cooled in an ice bath before collecting by filtration and drying under high vacuum. The two solids were combined to provide the product (82.1 g, 71%) as white solid.
Reaction SMILES: O.[C:2](S)(C)([CH3:4])[CH3:3].[CH3:7][C:8](N=N[C:14]([C:17]#N)([CH3:16])[CH3:15])([C:10]#[N:11])C.[C:19](#N)C=C>>[C:10](#[N:11])[CH:8]=[CH2:7].[CH2:19]=[CH:17][C:14]1[CH:15]=[CH:4][CH:2]=[CH:3][CH:16]=1
Reactant: CC(C)(C)S
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C=CC#N
Solvent: O
Product: C=Cc1ccccc1
Temperature: 65 °C

Procedure:
168.7 Parts of demineralized water were added to a reactor. The reactor was sealed and purged with nitrogen. To a separate container were added 26.9 parts of demineralized water, 1.5 parts GAFAC RE-610 and 0.02 part citric acid monohydrate, and the components were mixed until dispersed. To a third container were added 21.6 parts styrene and 67 parts acrylonitrile and the components were mixed for 10 minutes. The aqueous solution of GAFAC RE-610 and citric acid were then added to the reactor by vacuum and the contents of the reactor heated with agitation. 15.2 Parts of elastomer were then added by vacuum followed by 20.3 parts demineralized rinse water. While heating, the reactor was purged with nitrogen. A mixture of monomer precharge consisting of 0.4 part styrene and 8.43 parts of acrylonitrile were added to the reactor by vacuum, and this was followed by the addition of 20.3 parts of demineralized water. The nitrogen purge was again repeated, and the final pressure in the reactor was maintained at a vacuum of 10 inches of Hg. After the temperature of the reactor was stabilized at 60°C, 0.1 part of Vazo 52 dissolved in 1.0 part acrylonitrile was added to the reactor with vacuum, followed by 0.33 part acrylonitrile as a rinse. 0.75 Part of water was then used to rinse the acrylonitrile into the reactor, and reaction time was measured subsequent to this point. After fifteen minutes of reaction time, the balance of the monomer mixture and the t-butyl mercaptan were pumped into the reactor through separate lines over a period of 360 minutes. At 165 minutes of reaction time, 0.3 parts of Vazo 52 dissolved in 0.33 parts of acrylonitrile were added to the reaction mixture by means of a vacuum, and this was followed by 0.33 parts of acrylonitrile and 0.75 parts of water. At 285 minutes of reaction time, the above addition of Vazo 52 and acrylonitrile was repeated, and the temperature was then raised to 65°C after 315 minutes. After all the monomers and the mercaptan had been added, the lines were purged with 0.75 part demineralized water and the temperature was maintained at 65°C for an additional 30 minutes.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](C)([CH3:13])[C:11]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:17](=[O:20])([O-])[O-:18].[K+].[K+]>CO>[CH2:1]([O:8][CH2:9][C:10]([CH3:13])([CH3:11])[C:17]([OH:18])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)COCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(COCc1ccccc1)C(=O)O
Temperature: 140 °C
Reaction time: 22 h
Yield: 98.8 %

Procedure:
3-Benzyloxy-2,2-dimethylpropionitrile (2.0 g, 10.6 mmol), potassium hydroxide (31.2 g, 86%, 479 mmol) and potassium carbonate (1.13 g, 82 mmol) were dissolved in methanol (340 ml), concentrated under reduced pressure. The resulting residue was heated at 140° C. (bath temperature) under nitrogen atmosphere, and stirred for 22 hours. The reaction mixture was dissolved in water, cooled in an ice-water bath, followed by controlling at pH of 1 with hydrochloric acid (36%) added thereto. The organic matter was extracted with diethyl ether, washed with saturated brine, dried on anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure to obtain the entitled compound (2.18 g, 99%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:33][CH3:34])=[N:4][C:5]([N:9]2[CH2:17][C@@H:16]3[C@@:11]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([N:12]=[C:13]([NH:18]C(=O)C4C=CC=CC=4)[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8].N1C=CC=CC=1.[ClH:41].CON>C(O)C>[CH:7]([NH2:6])([CH3:8])[CH3:2].[ClH:41].[F:1][C:2]1[C:3]([O:33][CH3:34])=[N:4][C:5]([N:9]2[CH2:17][C@@H:16]3[C@@:11]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([N:12]=[C:13]([NH2:18])[S:14][CH2:15]3)[CH2:10]2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(N2C[C@H]3CSC(NC(=O)c4ccccc4)=N[C@@]3(c3ccccc3)C2)nc(C)c1F
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)N
Product: COc1nc(N2C[C@H]3CSC(N)=N[C@@]3(c3ccccc3)C2)nc(C)c1F
Temperature: 55 °C
Yield: 10 %

Procedure:
To a solution of N-[(4aR,7aS)-6-(5-fluoro-4-methoxy-6-methyl-pyrimidin-2-yl)-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (68 mg, 0.14 mmol) in ethanol (5.0 mL) is added pyridine (0.115 mL, 1.42 mmol) and O-methylhydroxylamine hydrochloride (118 mg, 1.42 mmol). The mixture is heated to 55° C. for 16 hours, cooled to ambient temperature, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with a gradient of 0 to 100% of hexane/ethyl acetate: 10% isopropyl amine to give the free base form of the title compound as a colorless oil. Dissolve this residue in dichloromethane (3 mL) and add 4 N HCl in dioxane (2 mL) and stir for 5 minutes. The solution is then concentrated to give the title compound as an off white solid (50 mg, 86%). ES/MS (m/e) 374.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=[O:19]>>[F:1][C:2]1[C:3]([CH:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[OH:19])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1
Reactant: O=Cc1ccc2ccccc2c1
Product: OC(c1ccc2ccccc2c1)c1ncccc1F

Procedure:
In the manner as described in Production example 1 while using 5.2 mL of 3-fluoropyridine and 10.2 g of 2-naphthaldehyde as starting materials, 3.8 g of the title compound was obtained as pale yellow needle crystals.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[NH:8][Si](C)(C)C.[Br:15][C:16]1[S:17][C:18]([C:29]#[N:30])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:20]=1.Cl>C(OCC)C.C1COCC1>[Br:15][C:16]1[S:17][C:18]([C:29](=[NH:8])[NH2:30])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:20]=1
Reactant: N#Cc1sc(Br)nc1-c1ccc(Cl)cc1Cl
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: N=C(N)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.5 M n-Butyllithium in hexanes (1.20 mL, 2.99 mmol) was added dropwise to a solution of hexamethyldisilazane (0.61 mL, 2.9 mmol) in diethylether (5 mL) at 0° C. The mixture was stirred for 30 mins at 0° C. and 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carbonitrile (400 mg, 1.0 mmol) in THF (50 mL) was added. After stirring at rt for 2 hours LCMS indicated complete conversion. The reaction mixture was poured to a cold 2N HCl (10 ml) and was extracted with diethylether (2×20 mL). The aqueous phase was adjusted to pH˜10 with NH4OH and was extracted with DCM (3×30 mL). Combined DCM extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title compound which was used directly in the next step (0.360 g, 80%). LCMS: (FA) ES+, 350, 352, 354.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])=[O:5].[OH-].[K+].CI.[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([N:6]([CH2:26][O:27][CH3:28])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:8])=[O:5]
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Reactant: COCCl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CI
Product: COCN(C(=O)Nc1ccc(Cl)cc1)C(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.3 g of N-(2,6-dichlorobenzoyl)-N'-(4-chlorophenyl)-urea and 1.88 g of powdered potassium hydroxide (90%) are dissolved 40 ml of dimethyl formamide, after which 4.7 g of methyl iodide are added drop by drop to the clear solution. The resulting reaction is exothermic. After stirring for two hours the solution is diluted with ice water and the solid substance is isolated. Yield 10.3 g. Melting point 124°-126°C. In a completely similar manner but using methoxymethylchloride instead of methyliodide, N-(2,6-dichlorobenzoyl)-N-(methoxymethyl)-N'-(4-chlorophenyl)-urea is produced. Melting point 121.5°-122.5°C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(Br)C=C>C1COCC1>[CH2:3]([CH:18]1[CH2:19][C:14]([N:13]([CH3:27])[CH3:12])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16][C:17]1=[O:20])[CH:2]=[CH2:1]
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1CC(c2ccccc2)(N(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at −30° C. (bath temperature). The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethyl-amino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (20 ml), was added in drops within 15 min. The batch was left for 30 min at −78° C. Then, allyl bromide (2.6 ml, 30 mmol), dissolved in dry THF (20 ml), was added in drops within 1 min. The reaction mixture was stirred for 10 min at −78° C., then the cooling was removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated NH4Cl solution (2×40 ml). The organic phases were then mixed with 1N HCl (30 ml) and thoroughly shaken out. The acid aqueous phase was separated and the organic phase was washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 2 N NaOH (70 ml). An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. The more non-polar diastereoisomer of the ketone was isolated from the residue (2 g) with a yield of 540 g (22%) by means of chromatographic purification [silica gel 60 (50 g); cyclohexane/ethyl acetate 1:10 (700 ml)]. The more polar diastereoisomer was obtained with a yield of 470 mg (19%).