Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([CH3:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CON(C)C(C)=O
Reactant: Cc1cc(Br)ccc1C(C)(C)C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)C#N)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a stirred solution of 2-(4-bromo-2-methylphenyl)-2-methylpropanenitrile (3.1 g, 13.0 mmol) in anhydrous THF (75 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (7.16 mL, 14.3 mmol). This reaction mixture is stirred at that temperature 10 min., then N-methoxy-N-methyl-acetamide (2.77 mL, 26.0 mmol) is added and the solution is then warmed up to room temperature over 1 h. Acidic brine (30 mL of brine, 15 mL of 3% HCl aq) is then slowly added and the solution extracted with EtOAc (3×100 mL). The organic layer is dried with MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash-chromatography using a 5 to 20% EtOAc in hexane gradient to provide the expected product 2-(4-acetyl-2-methylphenyl)-2-methylpropanenitrile (1.77 g, 68%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.84-7.74 (2H, m), 7.43-7.40 (1H, m), 2.70 (3H, s), 2.60 (3H, s), 1.81 (6H, s).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>ClCCl>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and N-(4-aminophenyl)methanesulfonamide (prepared according to the method described by Lee et al. in Bioorg. Med. Chem. Lett. 2005, 15, 4136-4142), the title compound was obtained as a white solid after trituration in dichloromethane.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)(=[O:25])[CH3:24]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)OCCCCBr
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.5 g, 41 mmol), K2CO3 (7.2 g, 51 mmol), and 4-bromobutyl acetate (10 g, 51 mmol) in acetontrile (200 ml) was heated at reflux for 3.5 hours. At the end of the reaction, the solution was cooled and filtered. The inorganic salt was washed with DCM (50 ml). The organic solvent was removed. The residue was purified on a flash chromatography column (packed with Sorbsil C30 silica gel, 100 g, eluted with DCM, 1 liter, increasing methanol from 2 to 4%, 2.51). The material thus purified weighed 12.92 g (89%). A small sample (1.67 g) was dissolved in ethanol and treated with 1 equivalent of fumaric acid (580 mg) in ethanol to yield white crystals: 1.8 g, m.p.=142°-143° C..
Reaction SMILES: [Br-:1].C1(C(O)(C2C=CC=CC=2)C(O[C@@H]2C3CC[N+](CC(=O)NC4C=NC=CN=4)(CC3)C2)=O)CCCC1.[Br-].O[C@@H]1C2CC[N+](CC(=O)NC3C=NC=CN=3)(CC2)C1.[Br-].[OH:57][C@@H:58]1[CH:63]2[CH2:64][CH2:65][N+:60]([CH2:66][C:67](=[O:75])[NH:68][C:69]3[CH:74]=[CH:73][N:72]=[CH:71][N:70]=3)([CH2:61][CH2:62]2)[CH2:59]1.[CH:76]1([C:82]([OH:92])([C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[C:83](O)=[O:84])[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]1>>[Br-:1].[CH:86]1([C:82]([OH:92])([C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:83]([O:57][C@@H:58]2[CH:63]3[CH2:64][CH2:65][N+:60]([CH2:66][C:67](=[O:75])[NH:68][C:69]4[CH:74]=[CH:73][N:72]=[CH:71][N:70]=4)([CH2:61][CH2:62]3)[CH2:59]2)=[O:84])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccncn1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1cnccn1
Agent: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCC1)C2)Nc1cnccn1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)C1CCCCC1)C2)Nc1ccncn1

Procedure:
This compound is prepared analogously to (R)-3-(2-Cyclopentyl-2-hydroxy-2-phenyl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Example 15) by replacing (R)-3-Hydroxy-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo-[2.2.2]octane bromide (Intermediate H) with (R)-3-Hydroxy-1-(pyrimidin-4-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate Q) and by replacing cyclopentyl-hydroxy-phenyl-acetic acid with cyclohexyl-hydroxy-phenyl-acetic acid, yielding the titled compound as a diastereomeric mixture. (M+ 479.5).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Yield: 100.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (367 mg, 0.643 mmol) prepared in Example 10a, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (304 mg, 99%) as a colorless solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:29][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3cccc(C(F)(F)F)c3)C2)CC1
Reactant: NC(=NO)c1cccc(F)c1
Product: N#CC1CCN(C(=O)N2CC(c3cccc(C(F)(F)F)c3)CC(c3nc(-c4cccc(F)c4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of the compound from Example 152A and 56 mg (0.37 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 87 mg (68% of theory).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][C:9]3[S:10][C:11]([C:16]([NH2:18])=[O:17])=[N:12][C:13]=32)=[CH:4][C:3]=1[F:19].[F:20][CH2:21][C:22]([CH3:26])([OH:25])[C:23]#[CH:24]>CS(C)=O.C(N(CC)CC)C.O>[F:19][C:3]1[C:2]([C:24]#[C:23][C:22]([OH:25])([CH3:26])[CH2:21][F:20])=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:16]([NH2:18])=[O:17])[S:10][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)CF
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCc1sc(C(N)=O)nc1-2)CF

Procedure:
The title compound was prepared according to a procedure similar to that described in Procedure G. Into a 10-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of 13-bromo-12-fluoro-9-oxa-5-thia-3-azatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2(6),3,10,12-pentaene-4-carboxamide (200 mg, 0.58 mmol, 1.00 equiv), 1-fluoro-2-methylbut-3-yn-2-ol (360 mg, 1.76 mmol, 3.00 equiv) and Pd(PPh3)Cl2 (82 mg, 0.20 equiv) in DMSO (0.5 mL) and triethylamine (0.5 mL). The final reaction mixture was irradiated with microwave radiation for 1 h at 70° C. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 3×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM:MeOH (10:1). This resulted in 0.06 g (28%) of 8-Fluoro-9-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide. LC-MS: (ES, m/z): 365[M+H]+; 1H-NMR: (400 MHz, CD3OD, ppm) δ 8.708 (d, 1H), 6.857 (d, 1H), 4.427 (t, 2H), 4.410 (d, 2H), 3.442 (t, 2H), 1.601 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:47]=[CH:46][C:24]4[O:25][CH2:26][C:27]5[CH:40]=[C:39]([CH2:41][CH2:42][C:43](=[O:45])[CH3:44])[CH:38]=[CH:37][C:28]=5[CH:29]([O:30]C5CCCCO5)[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][C:10]=1[F:48].C(O)(=O)C>O1CCOCC1.O>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:47]=[CH:46][C:24]4[O:25][CH2:26][C:27]5[CH:40]=[C:39]([CH2:41][CH2:42][C:43](=[O:45])[CH3:44])[CH:38]=[CH:37][C:28]=5[CH:29]([OH:30])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][C:10]=1[F:48]
Reactant: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2OC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
0.02 ml of trifluoroacetic acid was added to 0.73 g of 2-(7-chloro-6-fluoroquinolin-2-yl)methoxy-8-(2-acetylethyl)-11-(2-tetrahydropyranyloxy)-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 74 dissolved in a mixed solution of 5 ml of dioxane and 2 ml of water, the mixture was stirred at room temperature for 15 minutes, 4 ml of acetic acid was added to the mixture and the mixture was stirred for 10 hours. 80 ml of water was added to the reaction mixture and insolubles were removed by filtration. The residue was dissolved in chloroform and the organic layer was washed with water and dried over anhydrous sodium sulfate. After the solvent was removed, the residue was washed with a mixed solution of acetone and ether to obtain 0.41 g of the title compound.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]([CH3:20])([CH3:19])[C:16](Br)=[O:17].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.O>[Br:14][C:15]([CH3:20])([CH3:19])[C:16]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][C:4]([C:16](=[O:17])[C:15]([Br:14])([CH3:20])[CH3:19])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)=[O:17]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)Br)cc2)cc1

Procedure:
To a solution of 5 g (29.37 mmols) of diphenylether and 15.23 g (64.61 mmols) of alpha-bromoisobutrylbromide (purity 97.5% by weight) in 50 ml of dichloromethane in about 30′ 8.61 g (64.61 mmols) of aluminum trichloride were added, maintaining the temperature between 0° and 5° C. After 1.5 h the reaction mixture was poured in a mixture of 200 ml of water and ice and 4 ml of 37% HCl. The organic phase was separated and washed with brine, dried on sodium sulphate, and filtered, A sample obtained after evaporation of the solvent was analysed.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8](C)=[CH:7][C:3]=1[C:4]([Cl:6])=[S:5].ClCl.[CH:15]([Cl:18])([Cl:17])[Cl:16]>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:15]([Cl:18])([Cl:17])[Cl:16])=[CH:7][C:3]=1[C:4]([Cl:6])=[S:5]
Reactant: ClC(Cl)Cl
Reactant: Cc1cc(C(=S)Cl)c(Cl)cc1Cl
Agent: ClCl
Product: S=C(Cl)c1cc(C(Cl)(Cl)Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-5-methylthiobenzoyl chloride (25 g.; 0.097 mole) in chloroform (1.30 ml.) is cooled in ice water to 20° C. and irradiated with a 200 watt bulb while a slow stream of chlorine is bubbled into the reaction mixture for four hours. The reaction mixture is stirred at 25° C. for 18 hours; then the solvent is removed by distillation at reduced pressure. The 2,4-dichloro-5-trichloromethylthiobenzoyl chloride which remains (14.0 g.; 40%) melts at 79°-81° C. after recrystallization from hexane.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCCCCC.[C:10]([C:14]1[NH:15][C:16](=[C:19]([C:33]#[N:34])[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][C:29]([O:31]C)=O)[N:21]=2)[S:17][CH:18]=1)([CH3:13])([CH3:12])[CH3:11].O>ClCCCl.C(Cl)Cl>[C:10]([C:14]1[NH:15][C:16](=[C:19]([C:33]#[N:34])[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][C:29]([N:2]([CH3:3])[CH3:1])=[O:31])[N:21]=2)[S:17][CH:18]=1)([CH3:11])([CH3:13])[CH3:12]
Reactant: CNC
Reactant: COC(=O)CCNc1nccc(C(C#N)=C2NC(C(C)(C)C)=CS2)n1
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)CCNc1nccc(C(C#N)=C2NC(C(C)(C)C)=CS2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of dimethylamine (0.051 mL, 1 mmol) in DCE was added a solution of TMA 2M in hexane (499 mmol, 1 mmol) and the mixture was stirred 30 min at r.t. To this solution was added a solution of methyl N-{4-[(4-tert-butyl-1,3-thiazol-2(3H)-ylidene)(cyano)methyl]pyrimidin-2-yl}-beta-alaninate (72 mg, 0.2 mmol) in DCE and the mixture was refluxed under inert atmosphere overnight then stirred for a week at r.t. The mixture was diluted with DCM then water was added. The suspension was filtered through celite. The filtrate was washed with aqueous NaHCO3 5% (×2) then brine and it was dried over MgSO4. The solvent was removed under reduced pressure affording the title compound as yellow solid (HPLC max plot 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[S:10][CH2:9][CH:8]([N:17]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]3)[CH2:7][C:6]2=1.[O:24]=[C:25]1[NH:30][C:29]2[CH:31]=[C:32]([CH:35]=O)[CH:33]=[CH:34][C:28]=2[O:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[S:10][CH2:9][CH:8]([N:17]3[CH2:18][CH2:19][CH:20]([NH:23][CH2:35][C:32]4[CH:33]=[CH:34][C:28]5[O:27][CH2:26][C:25](=[O:24])[NH:30][C:29]=5[CH:31]=4)[CH2:21][CH2:22]3)[CH2:7][C:6]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CS3
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NCc2ccc4c(c2)NC(=O)CO4)CC1)CS3

Procedure:
The titled compound is prepared as a light yellow solid (21 mg, 28% yield) following Scheme 1 and in analogy to Example 2 using 1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (27 mg, 0.14 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CS([C:18]1[N:23]=[CH:22][C:21]2=[CH:24][CH:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]2[N:19]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18]2[N:23]=[CH:22][C:21]3=[CH:24][CH:25]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:33]([CH3:38])[S:34]([CH3:37])(=[O:36])=[O:35])[N:20]3[N:19]=2)=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: Nc1ccc(F)c(N2CCOCC2)c1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(F)c(N4CCOCC4)c3)nn12)S(C)(=O)=O
Yield: 37.7 %

Procedure:
4-Fluoro-3-morpholin-4-yl-phenylamine (50.0 mg, 0.255 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (46.4 mg, 0.127 mmol) and N,N-Diisopropylethylamine (0.0666 mL, 0.382 mmol) were dissolved in 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced and the crude residue was isolated and purified by Gilson prep HPLC to afford 23.77 mg of N-{2-[2-(4-Fluoro-3-morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=497.1. 1H NMR (400 MHz, DMSO, d6) δ 9.36 (s, 1H), 8.97 (s, 1H), 7.72 (m, 1H), 7.67 (m, 1H), 7.54 (m, 3H), 6.96 (m, 3H), 6.87 (m, 1H), 3.59 (m, 4H), 3.07 (s, 3H), 2.79 (s, 3H), 2.55 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Br)c2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A solution of 168 mg (0.47 mmol) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-hydroxy-piperidine-1-carboxylate and 157 mg (0.71 mmol) of 2-bromomethylnaphthalene in 2 ml of dimethylformamide was treated with 28 mg (0.7 mmol) of sodium hydride (60% dispersion in refined oil) and the mixture was stirred at room temperature for 3 hours. Subsequently, the reaction mixture was partitioned between ethyl acetate and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:4 mixture of ethyl acetate and hexane as the eluent. There were obtained 173 mg (74% of theory) of tert-butyl (3RS,4RS)-4-(3-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow oil; MS: 439, 441 (M-C4H8)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]CC1C=CC=CC=1)[CH:11]=[CH:10][CH:9]=2)=[O:5]>C(OCC)(=O)C.[Pd]>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
158 (8 g, 20 mmol) is dissolved in 80 ml of ethyl acetate and, after addition of 5% Pd—C (700 mg), the mixture is hydrogenated at room temperature for 7 hours. The mixture is filtrated over celite to remove the catalyst and evaporated. The solid is suspended in ether/hexane and filtered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:29][CH3:30])[CH:27]=[CH2:28]>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:29]([CH2:26][CH:27]=[CH2:28])[CH3:30])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCCBr)ccc21
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCCN2C(=O)OC(C)(C)C

Procedure:
In analogy to example 2.6, 6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and N-allyl-methylamine were converted to yield 6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as colorless gum, MS: 403 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1([C:17]([O:19]CC)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].OO>C(O)(C)(C)C>[C:1]([O:5][C:6]([CH2:8][CH2:9][C:10]1([C:17]([OH:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 44.6 %

Procedure:
To a suspension of 2-[2-(tert-butoxycarbonyl)ethyl]-2-ethoxycarbonylcyclohexanone (see Preparation 10) (1.0 g, 3.35 mmol) and sodium hydrogen carbonate (0.281 g, 3.35 mmol) in tert-butanol (2.0 ml) was added, in four portions over a period of 1.5 hours, a 30% aqueous solution of hydrogen peroxide (4×0.11 ml, 4.0 mmol) at 40° C. The mixture was stirred at 40° C. for 20 hours. A fifth charge of a 30% aqueous solution of hydrogen peroxide (0.11 ml) and a further quantity of sodium hydrogen carbonate (0.281 g, 33.5 mmol) was added, and the mixture stirred at 40° C. for 8 hours. The mixture was partitioned between hexane (40 ml) and 5% aqueous sodium sulphite solution (25 ml) and the layers separated. The hexane layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 5×40 ml). The combined aqueous extracts were acidified to pH 2-3 with 5.ON aqueous hydrochloric acid solution and extracted with dichloromethane (3×25 ml). The combined dichloromethane extracts were washed with distilled water (25 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as an oil, (0.362 g, 44.6%). Rf. 0.29 (silica, hexane/ethyl acetate 2:1). Analysis %: Found: C, 64.78; H, 9.39; C1H22O4 requires: C, 64.44; H, 9.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH:20]([OH:21])[CH2:19][NH:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(#N)C.C1CCN2C(=NCCC2)CC1.Cl[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[C:39]([C:49]([F:52])([F:51])[F:50])[N:38]=1>CO.CCOC(C)=O.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C@@H:16]3[C@@H:20]([OH:21])[CH2:19][N:18]([C:37]4[C:46]5[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=5)[N:40]=[C:39]([C:49]([F:51])([F:52])[F:50])[N:38]=4)[CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CNCC2O)CC1
Reactant: COc1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc2nc(C(F)(F)F)nc(N3C[C@H](O)[C@@H](N4CCN(C(=O)c5ccc(Cl)cc5)CC4)C3)c2c1
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To 0.326 mmoles of (4-Chloro-phenyl)-[4-(4-hydroxy-pyrrolidin-3-yl)-piperazin-1-yl]-methanone (synthesis described above in Example 5), add 1.6 mL acetonitrile and 1.63 mmoles of DBU. The stirred solution was cooled in ice and then 0.358 mmoles of 4-chloro-6-methoxy-2-trifluoromethyl-quinazoline was added and the reaction mixture was allowed to stir for a period of 2.5 hours. For the workup, the reaction mixture was diluted with methanol and concentrated on the rotavap. To the concentrate about 35 mL of water was added and was extracted with 40 mL EtOAc. The organic layer was separated and washed with 35 mL of 1M aq K2CO3 soln, and brine, dried over MgSO4 and excess solvent was removed on rotavap to yield a crude oil. This was diluted with about 2 mL EtOAc and about 8 mL ether was added and the white solid obtained was filtered off and vacuum dried to give the title compound in 80% yield. LC-MS: m/z=536 (M++1)