Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2)[C:9]#[N:10].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>C(OCC)C.C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(Cl)Cl>[F:5][C:6]1[CH:7]=[C:8]([C:9]2([NH2:10])[CH2:2][CH2:1]2)[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)[N:17]=2
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: NC1(c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Ethylmagnesium bromide (1 M solution in t-butyl methyl ether) (0.764 mL, 0.764 mmol) was added at −78° C. to a solution of 3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)benzonitrile (0.113 g, 0.306 mmol) and titanium (iv) isopropoxide (0.098 mL, 0.336 mmol) in ethyl ether (3 mL) and toluene (3 mL) under argon. After stirring at −78° C. for 10 min, the yellow solution was allowed to warm to room temperature (1 h), during which boron trifluoride diethyl etherate (0.023 mL, 0.187 mmol) was added. After the reaction mixture was stirred for 1 h, 1 N HCl (ca. 0.5 mL) and CH2Cl2 were added. NaOH (10% aq, ca. 1 mL) was added to the resulting two clear phases and the mixture was extracted with CH2Cl2. The combined CH2Cl2 layers were dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 10% MeOH/CH2Cl2 failed to give a pure batch of 1-(3-fluoro-4-(5-(1-phenyl-cyclopropyl)thiazolo-[5,4-b]pyridine-2-yl)phenyl)cyclopropanamine. Further purification on the reverse phase prep. HPLC provided the title compound as an off-white solid. MS (ESI) m/z: Calculated: 401.1; Observed: 402.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:83][C@H:84]1[O:89][C@@H:88]([CH3:90])[CH2:87][NH:86][CH2:85]1>CN(C=O)C.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:86]3[CH2:85][C@H:84]([CH3:83])[O:89][C@H:88]([CH3:90])[CH2:87]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Br)cc2)cn1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(6-methyl-pyridine-3-carbonyl)-phenyl]-benzenesulfonamide.0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), cis-2,6-dimethylmorpholine 0.37 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 3 ml DMF, followed by workup and HPLC purification to yield yellow title compound.
Reaction SMILES: [CH3:1][N:2]1[C:9](=O)[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].P(Cl)(Cl)([Cl:14])=O>O>[Cl:14][C:9]1[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6](=[O:7])[CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: O
Product: Cn1c(Cl)cc(=O)n(C)c1=O

Procedure:
To 110 g of the 1,3-dimethylbarbituric acid was added 32 ml of water, and 800 ml of phosphorus oxychloride was added dropwise thereto. After heating at reflux for 1.5 hours, the phosphorus oxychloride was distilled away under normal pressure, and the residue, while hot, was poured onto ice. The precipitated crystals were collected by filtration. The filtrate was extracted three times with chloroform and dried over anhydrous sodium sulfate. The chloroform was then removed by distillation, and the resulting residue was combined with the aforesaid crystals. Recrystallization from water gave 80 g of 6-chloro-1,3-dimethyluracil.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1([C:20]([NH:22][CH3:23])=[O:21])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C.Cl.ClCCl>[CH3:1][NH:8][C:9]1([C:20]([NH:22][CH3:23])=[O:21])[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]1
Reactant: CNC(=O)C1(N(C)Cc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)C1(NC)CN(C(=O)OC(C)(C)C)C1
Yield: 93.3 %

Procedure:
10% wt Palladium on charcoal (160 mg) in ethyl acetate (2 ml) was added to a solution of tert-butyl 3-[benzyl(methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate (580 mg, 1.74 mmol) in ethanol (45 ml). After the addition of a few drops of saturated hydrogen chloride in dichloromethane, the reaction mixture was stirred at room temperature under 3 bars of hydrogen for 3 hours. Filtration of the catalyst and concentration under reduced pressure gave tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate (395 mg, 93%) as a white solid, which was used without further purification in the next step. 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 2.30 (s, 3H), 2.84 (s, 3H), 3.68 (d, 2H), 4.27 (brs, 2H), 7.05 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][NH2:11].[O-]S([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:11][CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CN=Cc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
In 30 ml of toluene, 0.8 g (5.7×10-3 moles) of 6-chloropyridine-3-aldehyde and 10 g of Na2S4 were mixed and while the mixtures was stirred, a 40% aqueous solution of methylamine (1.4 g, 1.1×10-2 mole) was added dropwise over 30 minutes, followed by addition of 10 g of MgSO4. The mixture was allowed to stand at room temperature overnight, after which it was filtered. The filtrate was concentrated to give 0.6 g (yield 68%) of N-(6-chloro-3-pyridylmethylidene)methylamine as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.[N:39]1([CH2:45][C:46]([N:48]2[CH2:52][CH2:51][CH2:50][CH2:49]2)=[O:47])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][C:46](=[O:47])[N:48]4[CH2:49][CH2:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 20% methanol in carbon dioxide). LR-MS: 729.4 [(M+H)+]
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[CH2:36][S:35]2)[CH:32]=1)(=[O:26])[CH3:25]>>[C:24]([C:27]1[CH:28]=[CH:29][C:30]([NH:47][CH2:48][CH3:49])=[C:31]([N:33]=[C:34]2[N:38]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:37](=[O:46])[C:36](=[C:14]3[N:13]([CH3:12])[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=4[S:15]3)[S:35]2)[CH:32]=1)(=[O:26])[CH3:25]
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SCC(=O)N1Cc1cccnc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-ium p-toluenesulfonate with 2-(5-acetyl-2-ethylaminophenylimino)-3-pyridin-3-ylmethyl-thiazolidin-4-one. MS(ESI): 520 (MH+).
Reaction SMILES: C(S([C:6]1[CH:34]=[CH:33][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:20]([CH:30]([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=O)=O)C.[CH3:35][O:36][C:37](=[O:46])C1C=CC(CN)=CC=1>>[CH:30]([C@H:20]1[C:17]2=[N:18][CH:19]=[C:14]([C:12](=[O:13])[NH:11][CH2:10][C:9]3[CH:33]=[CH:34][C:6]([C:37]([O:36][CH3:35])=[O:46])=[CH:7][CH:8]=3)[CH:15]=[C:16]2[CH2:22][N:21]1[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])([CH3:32])[CH3:31]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(C(=O)OC(C)(C)C)[C@H]3C(C)C)cc1
Reaction time: 0.03 h

Procedure:
Procedure same as that for tert-butyl(S)-3-((4-(ethylsulfonyl)benzyl)carbamoyl)-7-isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, using methyl4-(aminomethyl)benzoate as a starting material. LC-MS tR=1.61 min in 2 min chromatography, MS (ESI) m/z 454.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10]>>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][N:21]1[CH2:22][CH2:23][CH:18]([C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:24])[CH:17]=[CH:16][CH:15]=2)[CH2:19][CH2:20]1
Reactant: OCCCCCl
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 4-chloro-1-butanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 319.3 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(Cl)CCl.[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:36]([CH:40]=1)[C:37](O)=[O:38]>CN(C)C=O>[Br:31][C:32]1[C:33]([CH2:49][N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[CH:34][C:35]([O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[C:36]([CH:40]=1)[C:37]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:38]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1

Procedure:
Diisopropylethylamine (72.2 μl, 0.414 mmol), HOBT (38.0 mg, 0.248 mmol), 3-aminopyridine (29.2 mg, 0.310 mmol) and EDC (79 mg, 0.414 mmol) To a solution of 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 7; 84 mg, 0.207 mmol) in N,N-dimethylformamide was added. The reaction was stirred over the weekend, then the solvent was removed in vacuo. Purification by MDAP gave the title compound as a white solid. 30 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:14][CH:15]=3)[C:10]([CH2:29][CH2:30][O:31][N:32]=[CH:33][C:34]([OH:36])=[O:35])=[C:9]2[CH3:37])[CH:2]=1.FC(F)(F)C(O)=O.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51]C=2)C=C1.N1C=CC=C(CCl)C=1.[H-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:14][CH:15]=3)[C:10]([CH2:29][CH2:30][O:31][N:32]=[CH:33][C:34]([OH:36])=[O:35])=[C:9]2[CH3:37])[CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:14][CH:15]=3)[C:10]([CH2:29][CH2:30][O:31][N:32]=[CH:33][C:34]([O:36][C:48]3[CH:53]=[N:45][CH:51]=[CH:50][CH:49]=3)=[O:35])=[C:9]2[CH3:37])[CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Agent: Cc1c(CCON=CC(=O)O)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1cccnc1
Agent: ClCc1cccnc1
Agent: [H-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CCON=CC(=O)Oc2cccnc2)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1cccnc1

Procedure:
The title compound is prepared by reaction of glyoxylic acid-O-2-[1-(3-pyridylmethyl)-5-(quinol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime with trifluoroacetic acid to remove the t-BOC group followed by reaction of the indole intermediate with two equivalents of 3-pyridylmethyl chloride in the presence of a suitable base such as NaH to provide the intermediate glyoxylic acid 3-pyridyl ester-O-2-[1-(3-pyridylmethyl)-5-(quinol-2-ylmethoxy)-2-methylindol-3-yl]ethyl oxime which is subsequently saponified.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:12]([F:11])[CH:13]=2)[CH:7]=1
Reactant: COc1ccc(CCN)cc1F
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(OC)c(F)c2)n1
Yield: 90.5 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine [0.7 g, Intermediate (4)], 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.66 g, Intermediate (3)] and sodium bicarbonate (0.88 g) in EtOH (25 mL) is heated at 80° C. for three hours and poured into water (400 mL). The resulting solid is filtered and air dried affording (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3-fluoro-4-methoxyphenyl)-ethyl]amine [1.1 g, Intermediate (5)]. MS: 312 (M+H); 1H NMR (CDCl3): δ 6.9-7 (3H, m); 6.05 (1H, s); 3.95 (3H, s); 3.85 (3H, s); 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[CH:17]=[N:18][NH:19][CH:20]=1.O[CH:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][N:19]([CH:26]2[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Brc1cn[nH]c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
DIAD (1.18 ml, 6.0 ml) was added dropwise to a solution of 4-bromopyrazole (0.74 g, 5.0 mmol), 3-hydroxy-1-tert-butoxycarbonylpiperidine (1.00 g, 5.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) in THF (50 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was partitioned between water and ethyl acetate. The organic fractions were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50% EtOAc/Petrol) to give the product (1.46 g). MS: [M+H]+=332.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:1]([C:15]1[CH:14]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:10]=1[O:9][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCCCOc1ccc(OCCCC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCCCOc1ccc(OCCCC)c(C(C)=O)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
77 [ml] of acetyl chloride was added to 70.3 [g] of 1,4-di-n-butoxybenzene, 50.7 [g] of aluminum chloride was added while cooling on ice, and the reaction was carried out while stirring at -5° C. for 1 hour. The reaction liquor was poured into 1000 [ml] of water, and extracted twice with 500 [ml] methylene chloride. The extraction solution (i.e. the methylene chloride solution) was washed with water, and concentrated by evaporating off the methylene chloride as solvent under reduced pressure. Concentration of the extraction solution was continued until almost no further methylene chloride remained. The concentrated extraction solution was then subjected to chromatography on a silica gel column using a mixture of n-hexane and ethyl acetate (volume ratio of n-hexane:ethyl acetate=30:1) as eluent, and a 77.2 [g] yield of 2-acetyl-1,4-di-n-butoxybenzene was thereby obtained.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 80 °C
Yield: 96.8 %

Procedure:
A solution of dibenzofuran-4-yl-boronic acid (20.0 g, 94.3 mmol), (4-bromo-phenyl)-trimethyl-silane (21.62 g, 94.3 mmol), K2CO3 (39.1 g, 3 equiv., 283 mmol) in toluene (100 mL), ethanol (60 mL) and water (30 mL) was purged with nitrogen for 5 min (bubbled into solution) and treated with Pd(PPh3)4 (3.59 g, 2.9 mmol). After heating to 80° C. for 4 h, the solution was cooled to room temperature, poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic phase was washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (5-20% ethyl acetate in heptane) afforded (4-dibenzofuran-4-yl-phenyl)-trimethyl-silane as a colorless oil (28.9 g, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([O:10]C)=O)[C:5](=O)[CH2:4][CH2:3]1.Cl.[Cl:15][CH2:16][C:17](=[NH:19])[NH2:18].C[O-].[Na+]>CO>[Cl:15][CH2:16][C:17]1[N:19]=[C:8]([OH:10])[C:6]2[CH2:7][C:2]([CH3:1])([CH3:13])[CH2:3][CH2:4][C:5]=2[N:18]=1
Reactant: N=C(N)CCl
Reactant: COC(=O)C1CC(C)(C)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCc2nc(CCl)nc(O)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
To a solution of methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate (6.0 g, 33 mmol) and 2-chloroacetimidamide hydrochloride (4.6 g, 36 mmol) in methanol (30 mL) was added sodium methoxide (4.4 M in MeOH, 9.0 mL, 40 mmol). The reaction mixture was stirred at ambient temperature for three hours and then concentrated. The resulting residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. Purification by silica gel chromatography provided 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-ol (4.2 g, 57% yield) as a white solid. MS (ES) for C11H15ClN2O: 227 (MH+).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([NH:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]([CH3:28])[CH:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)O[O:37]1>CC(C)=O>[OH:37][N:8]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]([CH3:13])[CH:11]([NH:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]([CH3:28])[CH:9]1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Reactant: CC1(C)OO1
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)NC1C(C)C(c2ccccc2)N(O)C(c2ccccc2)C1C

Procedure:
Following the general procedure of Example 2 and using 8.56 g (18.5 mmol) of N-(2,6-diphenyl-3,5-dimethylpiperidin-4-yl)lauramide, prepared in Example 11, and 462 ml of a 0.04 molar solution of dimethyldioxirane (18.5 mmol) in acetone, the title compound is isolated in a yield of 7.37 g (70%) after purification by LC (silica gel; ethyl acetate:hexanes) as a white solid melting at 58°-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25].CCN(CC)CC>ClCCCl>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25]
Reactant: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with (3-chloro-4-isocyanato-phenyl)-acetic acid ethyl ester in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 d under reflux conditions to give the title compound as brown gum. MS: m/e=565.3 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[N:8][C:9]([C:14]([O:16]CC)=O)=[C:10]([OH:13])[C:11](=[O:12])[N:6]2[CH2:5][C:4](=[O:19])[N:3]1[CH3:20].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][C:23]=1[CH3:30]>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14]([C:9]2[N:8]=[C:7]3[N:6]([C:11](=[O:12])[C:10]=2[OH:13])[CH2:5][C:4](=[O:19])[N:3]([CH3:20])[N:2]3[CH3:1])=[O:16])=[CH:24][C:23]=1[CH3:30]
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N(C)N2C
Reactant: Cc1cc(CN)ccc1F
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CC(=O)N(C)N3C)ccc1F
Yield: 79.8 %

Procedure:
Reaction of intermediate 22, ethyl 1,2-dimethyl-7-hydroxy-3,6-dioxo-2,3,4,6-tetrahydro-1H-pyrimido[2,1-c][1,2,4]triazine-8-carboxylate, (0.050 g, 0.177 mmol) with 4-fluoro-3-methylbenzylamine (0.10 g, 0.72 mmol) as described in the preparation of example 1 gave 0.053 g (79% yield) of the title amide as white crystals. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.31 (3H, s, CH3), 3.27 (3H, s, NCH3), 3.30 (3H, s, NCH3), 4.56 (2H, d, J=5.9 Hz, NCH2), 4.67 (2H, s, CH2), 7.02 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.17 (1H, m, aromatic), 7.71 (1H, broad t, NH), 12.02 (1H, s, OH). MS (ESI+) m/z 376 [M+H+].