Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([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.[CH3:19][Mg]I.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 104 %

Procedure:
To a tetrahydrofuran solution (10 mL) of 1-benzhydrylazetidin-3-one (530 mg, 1.94 mmol), methylmagnesium iodide (0.84 M ether solution) (4.62 mL, 3.88 mmol) was added at 0° C. under a nitrogen stream, and the mixture was stirred for one hour at the same temperature. A saturated aqueous solution of sodium hydrogen carbonate (20 mL) was added to the reaction liquor, and the mixture was stirred for 15 minutes. Then, the reaction liquor was filtered through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, and then dried over anhydrous sodium sulfate. Sodium sulfate was separated by filtration, and the solvent was concentrated under reduced pressure. The obtained residue was purified by flash chromatography (Flash Chromatography System from Biotage AB, column size: 40S, ethyl acetate/n-hexane=1/4 to ethyl acetate), to obtain the title compound (511 mg, quant.) as an oily matter.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][O:5][C:4](=[O:7])[C:3]1=O.[ClH:10].[NH2:11][NH:12][C:13]([NH:15][NH2:16])=[NH:14].O>C(O)C>[ClH:10].[NH2:14][C:13]1[N:15]([NH2:16])[C:4](=[O:7])[C:3]([C:2]([CH3:9])([CH3:1])[CH2:6][OH:5])=[N:11][N:12]=1
Reactant: CC1(C)COC(=O)C1=O
Reactant: N=C(NN)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(CO)c1nnc(N)n(N)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Dihydro-4,4-dimethyl-2,3-furandione (2 g, 15.6 mmole) and 1,3-diaminoguanidine monohydrochloride (12.96 g, 15.61 immole) were dissolved in ethanol and the resulting solution heated to reflux temperatures. To the refluxing reaction mixture, was added water until a clear solution was obtained. The mixture was then refluxed overnight, cooled to room temperature and stored at -20° C. overnight. The product which separated was filtered and dried. It was crystallized from a mixture of ethanol and water to give 3,4-diamino-6-(1',1'-dimethyl-2'-hydroxyethyl)-1,2,4,-triazin-5(4H)-one hydrochloride (2.24 g, 61%), m.p. 221-222° C. (dec).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(N(CC)CC)C.O>ClCCl>[Br:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-phenylbenzene-1,2-diamine (6.08 g, 30 mmol) in anhydrous dichloromethane (˜100 mL), was added 2-bromobenzoylchloride (6.585 g, 33 mmol), followed by triethylamine (7.0 mL, 50 mmol) slowly with water bath cooling. After the additions, the whole was stirred at room temperature overnight. The resulting mixture was poured into water (˜150 mL) and extracted with dichloromethane (˜100 mL) twice. The organic phase was collected, dried over Na2SO4, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (10.7 g, in 92% yield).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[CH:26][C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[CH:26][C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cn1ncc(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC=C3C(=O)Nc4cc(C(=O)c5cccc(NC(=O)c6c(Cl)cnn6C)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A small screw cap test tube was charged with 4-Chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (50.53 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 32% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.ClC1C=CC=CC=1N1C(=O)C2[C@@H]3C(C)(C)[C@@](C)(CC3)C=2N1CC>>[CH2:22]([N:9]1[C:10]2[C:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[CH:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCn1c2c(c(=O)n1-c1ccccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Product: CC12CCC(c3c1n(Cc1ccccc1)n(-c1ccccc1Cl)c3=O)C2(C)C

Procedure:
Benzyl-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one was prepared from (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 10) and benzyl bromide using the procedure described above for the preparation of (4S,7R)-2-(2-chloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 9). APCI-MS (M+H) 393.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 5-cyclohexylpentanoic acid (63.50 g, 345 mmol) in N,N-dimethylformamide (0.5 ml) and dichloromethane (350 ml) was cooled to 5° C. and treated dropwise with oxalyl chloride (31.6 ml, 362 mmol) over 30 minutes. The mixture was stirred at 0° C. for 3 hours then the solvent was removed under reduced pressure to afford 5-cyclohexylpentanoyl chloride as a pale yellow solid (70.0 g).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4]1.[CH3:18][O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24](O)=[O:25])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:18][O:19][C:20]([NH:22][C@@H:23]([CH:27]([CH3:29])[CH3:28])[C:24]([N:6]1[CH2:7][C:3](=[O:2])[CH2:4][C@H:5]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:25])=[O:21]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C1CN[C@H](C(=O)OCc2ccccc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OCc1ccccc1)C(C)C
Reaction time: 2 h

Procedure:
(S)-Benzyl 4-oxopyrrolidine-2-carboxylate hydrochloride (1.92 g, 8.8 mmol), the acid (in this case (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid) (1.84 g, 10.56 mmol) and HATU (5.02 g, 13.2 mmol) were weighed out in a round bottom flask and dissolved in anhydrous DMF (44 mL). To this mixture was added DIPEA (6.82 g, 52.8 mmol) at room temperature and the mixture was stirred for 2 h. The crude mixture was diluted with EtOAc and washed respectively with brine, 10% Na2CO3 and brine again, and the mixture was dried over MgSO4, after filtration the mixture was concentrated down on rotovap. The residue was then purified on normal phase chromatography. (2.45 g, 74%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[N:4]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:10][S:11]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][S:11]([CH3:10])(=[O:13])=[O:12])[N:4]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cccc(O)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1cccc(OS(C)(=O)=O)n1

Procedure:
2,6-dihydroxypyridine hydrochloride (3 g) was suspended in dichloromethane (250 cm3) under an atmosphere of nitrogen at 0° C. The mixture was treated with methanesulphonyl chloride (3.5 cm3). The suspension was stirred and triethylamine (9.4 cm3) was added in aliquots over 15 minutes. The resulting mixture was stirred for 17 hours and poured onto brine. The organic layer was separated, washed twice with brine, dried over anhydrous magnesium sulphate, and the solvent evaporated under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:10]=2)[O:3]1
Reactant: ClCCN1CCOCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 4-(2-chloroethyl)morpholine hydrochloride (252 mg, 0.28 mmole, Aldrich, Cat. No. C42203), cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) in a sealed reaction vial was stirred at 90° C. overnight. LC/MS showed it worked well. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 50 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])=O)(C)(C)C.[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]1=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14].[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:20]1=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound obtained in example 16 (658 mg) was dissolved in 25% TFA/DCM solution (10 mL). The mixture was stirred on a magnetic stirrer for 4 hrs at room temperature. DCM and most of TFA were removed by rotary evaporation in vacuo. The foam obtained was dissolved in DCM (50 mL). The resultant mixture was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The solid obtained (380 mg) was dried in vacuo. 1H NMR (CDCl3, ppm) δ8.0-8.1 (m, 2H), 7.90-8.00 (m, 2H), 5.20-5.28 (m, 1H), 4.59-4.62 (m, 1H), 4.30-4.55 (m, 2H), 4.00-4.30 (m, 2H), 3.70-3.85 (m, 1H), 3.40-3.65 (m, 2H), 2.90-3.12 (m, 2H), 2.70-2.90 (m, 1H), 2.30-2.50 (m, 1H), 2.00-2.20 (m, 4H)
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].Cl[CH2:8][CH:9]([OH:15])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12].[Na]>O1CCOCC1.O>[OH:15][CH:9]([CH2:8][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:10][S:11]([OH:14])(=[O:13])=[O:12]
Reactant: CC(C)CCN
Reactant: O=S(=O)(O)CC(O)CCl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CCNCC(O)CS(=O)(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a 80° C. solution of isoamylamine (2.0 g, 22.9 mmol) in 1,4-dioxane (9 mL) and water (3 mL) was added via syringe pump (1 h addition) a solution of 3-chloro-2-hydroxy-propane sulfonic acid, sodium salt (3.04 g, 15.3 mmol) in 1,4-dioxane (9.5 mL) and water (0.5 mL). The solution was stirred overnight at 80° C. The solvent was evaporated. The product was passed through an ion exchange column (Dowex 50×8, 100 g, solvent: water). It was recrystallized in absolute EtOH and lyophilized. Yield: 27%. 1H NMR (H2O, 500 MHz) δ ppm 4.24 (m, 1H), 3.22 (m, 1H), 3.02 (m, 5H), 1.49 (m, 3H), 0.79 (d, 3H, J=6.3 Hz). 13C(H2O, 125 MHz) δ ppm 63.54, 54.89, 51.53, 46.48, 34.12, 25.46, 21.56, 21.46. ES-MS 226 (M+1).
Reaction SMILES: [NH2:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CC(O[Na])=O.[CH3:16][NH:17][C:18]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[Cl:31])[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1>CO.O.O>[CH2:3]([O:2][N:1]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31])[NH:17][CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC1(c2ccccc2Cl)CCCCC1=O
Reactant: NOCc1ccccc1
Agent: CC(=O)O[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC1(c2ccccc2Cl)CCCCC1=NOCc1ccccc1
Temperature: 25 °C

Procedure:
To as solution of NH2OCH2Ph. HCl and CH3COONa. H2O in MeOH:H2O (7:3) stirred at room temperature for 15 minutes, was added ketamine and the resulting solution was stirred at reflux for 16 hrs before cooling to room temperature. The reaction mixture was filtered and the filtrate was partitioned between CH2Cl2 and sat. NaHCO3 solution. The filtrate was extracted with CH2Cl2 (2×30 mL) and the combined organic layer was washed with brine solution. The organic layer was dried over anhydrous. Na2SO4 and concentrated under reduced pressure. The crude reaction mixture received was purified over silica gel column chromatography by eluting with initially CH2Cl2 and later with (1:9) MeOH:CH2Cl2 to receive benzoxime 4 as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.7 (d, J=8.06 Hz, 1H), 7.1-7.4 (m, 8H), 5.0-5.2 (q, J=8.2 Hz, 2H), 2.9-3.1 (m, 2H), 2.2-2.3 (m, 3H), 1.9-2.0 (m, 2H), 1.3-1.8 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 158.3, 138.7, 135.1, 132.1, 131.1, 129.9, 128.7, 128.4, 127.8, 127.6, 66.4, 38.8, 29.1, 26.0, 24.5, 22.1.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1CCC(=O)CC1)C1C=CC=CC=1.CS(N1CCNCC1)(=O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+].C([N:60](CC1C=CC=CC=1)[C@H:61]1[CH2:66][CH2:65][C@H:64]([N:67]2[CH2:72][CH2:71][N:70]([S:73]([CH3:76])(=[O:75])=[O:74])[CH2:69][CH2:68]2)[CH2:63][CH2:62]1)C1C=CC=CC=1>ClCCl.CO.[Pd].O>[CH3:76][S:73]([N:70]1[CH2:69][CH2:68][N:67]([C@H:64]2[CH2:65][CH2:66][C@H:61]([NH2:60])[CH2:62][CH2:63]2)[CH2:72][CH2:71]1)(=[O:74])=[O:75]
Reactant: CS(=O)(=O)N1CCN([C@H]2CC[C@H](N(Cc3ccccc3)Cc3ccccc3)CC2)CC1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CS(=O)(=O)N1CCNCC1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CCN([C@H]2CC[C@H](N)CC2)CC1

Procedure:
14 g (47 mmol) 4-dibenzylamino-cyclohexanone, 8.5 g (51 mmol) 1-methanesulphonyl-piperazine and 17.5 g (78 mmol) sodium triacetoxyborohydride are stirred in 250 ml dichloromethane for 4 hours at ambient temperature. Then the reaction mixture is combined with 200 ml of water and 20 g potassium carbonate. The organic phase is separated off, dried and evaporated to dryness. The residue is purified by chromatography. Yield: 4.8 g trans-isomer 4.8 g (11 mmol) trans-dibenzyl-[4-(4-methanesulphonyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 100 ml of methanol and 2 g palladium/charcoal (10%) are added. The mixture is hydrogenated at 50 psi and 50° C. Then the catalyst is suction filtered, the mother liquor is concentrated by evaporation. The precipitate formed is suction filtered and washed with diethyl ether. Yield: 2.4 g
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25](Cl)=[O:26])[CH3:21]>ClCl.N1C=CC=CC=1>[CH2:20]([O:22]/[CH:23]=[CH:24]/[C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2)=[O:26])[CH3:21]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CCO/C=C/C(=O)Cl
Agent: ClCl
Solvent: c1ccncc1
Product: CCO/C=C/C(=O)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of (±)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (3.06 g, 12.2 mmol, described in Intermediate 4) in CH2 Cl2 (100 mL) and pyridine (40 mL) was added a solution of (E)-3-ethoxyacryloyl chloride [Tietze et al., Synthesis, 1993, 1079-1080](1.64 g, 12.2 mmol) in CH2 Cl2 (100 mL). The resulting mixture was stirred at ambient temperature for 1 h, then concentrated to dryness in vacuo. The residue was suspended in H2O (350 mL) with sonication and the solid was isolated by filtration and dried to give the title compound. MS: m/z=350 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[CH2:17]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[CH2:17]([CH:25]1[CH2:26][CH2:27][N:28]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:29][CH2:30]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc(CCC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C(CN1CCC(CCc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-yl)-acetamide (Example 153a) and 4-phenethyl-piperidine according to the method described in Example 142b. Melting Point: 200-203° C. (diethylether)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:25]2[CH2:29][CH2:28][CH2:27][S:26]2(=[O:31])=[O:30])[CH:3]=1.[CH3:32][C:33]1([CH3:39])[O:37][C:36](=[O:38])[N:35]=[CH:34]1>>[O:30]=[S:26]1(=[O:31])[CH2:27][CH2:28][CH2:29][N:25]1[C:4]1[CH:3]=[C:2]([N:35]2[CH2:34][C:33]([CH3:39])([CH3:32])[O:37][C:36]2=[O:38])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reactant: CC1(C)C=NC(=O)O1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)OC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 48.3 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (761 mg) described in Preparation Example 180 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (392 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1([F:42])[CH2:35][CH2:34][CH2:33][N:32]([CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40])[CH2:31]1>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:32]3[CH2:33][CH2:34][CH2:35][C:30]([F:29])([F:42])[CH2:31]3)[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)/C=C/CN1CCCC(F)(F)C1
Product: Nc1ncnc(Oc2ccc(Oc3ccccc3)cc2)c1-c1cccc(NC(=O)/C=C/CN2CCCC(F)(F)C2)c1
Yield: 48 %

Procedure:
(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(3,3-difluoropiperidin-1-yl)but-2-enoic acid using Method E (48% yield). HPLC: 97%, RT=3.809 min. MS: m/z=558 [M+H]+, RT=1.92 min.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Yield: 55 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (1.92 g, 6.97 mmol) and 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline from the previous step (2.0 g, 6.97 mmol) were reacted in the manner described in Example 16C to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (2.00 g, 3.8 mmol, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.56 (s, 1H), 8.98 (s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.38 (t, 1H), 7.33 (s, 1H), 7.26 (d, 1H), 6.96 (d, 1H), 6.47 (s, 1H), 4.27 (t, 2H), 3.98 (s, 3H), 3.82 (t, 2H), 2.30-2.24 (m, 2H), 1.29 (s, 9H); LC-MS (ESI) m/z 526 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20](C)[C:21](=O)OC(C)(C)C)=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1.O1CCOCC1.[ClH:35]>>[ClH:35].[F:1][CH2:2][CH2:3][NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2ccc3nc(NCCF)sc3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CNc1ccc(-c2ccc3nc(NCCF)sc3c2)cc1
Yield: 74 %

Procedure:
Tert-butyl 4-(2-(2-fluoroethylamino)benzo[d]thiazol-6-yl)phenyl(methyl)carbamate (25 mg, 0.06 mmol) was treated with 4 mL of 4 M HCl dioxane solution for 2 h and concentrated. The residue was washed with ether (2×3 mL) and dried under high vacuum to afford N-(2-fluoroethyl)-6-(4-(methylamino)phenyl)benzo[d]thiazol-2-amine hydrochloride as a yellow solid (15 mg, 74%). 1H NMR (400 MHz, methanol-d4) δ 8.18 (s, 1 H), 7.91-7.88 (m, 2 H), 7.86-7.84 (m, 1 H), 7.67 (m, 3 H), 4.82 (t, J=4.8 Hz, 1 H), 4.70 (t, J=4/8 Hz, 1 H), 3.99 (t, J=4.4 Hz, 1 H), 3.93 (t, J=4.4 Hz, 1 H), 3.13 (s, 3 H); MS (ESI) m/z 302 (M+H+).