Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([CH3:27])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:19][C:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][C:9]([O:17][CH3:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH3:27]
Reactant: COc1ccc(C(=O)O)nc1-c1cccc(Cl)c1
Reactant: CC(C)(N)c1ncco1
Product: COc1ccc(C(=O)NC(C)(C)c2ncco2)nc1-c1cccc(Cl)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-methoxy-pyridine-2-carboxylic acid (Example 81 c) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=372.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:35])[CH2:13][CH:14]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[N:26][O:27][CH3:28])[CH2:21][CH2:20]3)=O)=[CH:8][CH:7]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])O.[Na+]>CS(O)(=O)=O>[CH3:28][O:27][N:26]=[C:22]1[C:23]2[C:19](=[CH:18][C:17]([C:15]3[O:35][C:12]([C:9]4[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:36])[CH3:1])=[CH:11][CH:10]=4)=[CH:13][C:14]=3[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]1
Reactant: CON=C1CCc2cc(C(=O)C(CC(=O)c3ccc(OCCN(C)C)cc3)c3ccncc3)ccc21
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CON=C1CCc2cc(-c3oc(-c4ccc(OCCN(C)C)cc4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
The product of Example 1 Step 4 (0.30 mg, 0.62 mmol) was added to a stirred suspension of phosphorus pentoxide (1 g) in dry methane sulphonic acid (5 ml). After stirring at room temperature for 2 hours the reaction mixture was cautiously poured into a stirred solution of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the organic phase washed with water and saturated brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (0.28 g, 96%); MS(ES+) m/e 468 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[N:44]([C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=1)=[C:45]=[O:46]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:43]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[N:37]1[CH2:42][CH2:41][N:40]([C:45]([NH:44][C:47]2[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][CH:48]=2)=[O:46])[CH2:39][CH2:38]1
Reactant: Clc1cnc2nc1Nc1ccc(N3CCNCC3)c(c1)CCc1cccc(c1)N2
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)N2CCN(c3ccc4cc3CCc3cccc(c3)Nc3ncc(Cl)c(n3)N4)CC2)cc1
Yield: 38 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-piperazin-1-yl-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene bis(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 38% yield. LCMS for C30H28ClN8O (M+H)+: m/z=551.0. 1H NMR (400 MHz, DMSO-d6): δ 9.46 (br s, 1H), 9.29 (br s, 1H), 9.09 (s, 1H), 8.13 (s, 1H), 7.97 (s, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.69 (s, 4H), 7.12-7.03 (m, 3H), 6.88-6.82 (m, 2H), 3.64 (br s, 4H), 2.98 (s, 4H), 2.84 (brs, 4H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[C:15](Cl)=[O:16]>CCCCCCC.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:9])[C:15](=[O:16])[C:14]1[CH:13]=[C:12]([C:11]([F:26])([F:25])[F:10])[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: CNc1cnccc1I
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (4-iodo-pyridin-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using a gradient of n-heptane:EtOAc (100:0 to 40:60) for the chromatographic purification. Light yellow solid (18%). MS (ESI): m/z=474.9738 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([NH2:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[C:1]([NH:8][C@H:9]([C:13](=[S:25])[NH2:15])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(N)=O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(N)=S
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Boc-valineamide (0.5 g) was stirred in dry THF at room temperature under argon. Lawesson's reagent (1.56 g, 0.6 eq) was added and the mixture was stirred overnight. The solvent was evaporated and the residue chromatographed (silica, 2.5% methanol/dichloromethane) to give the title compound as a white solid (0.373 g, 70%). NMR(CDCl3) δ 8.59 (1H, br s), 8.09 (1H, br s), 5.41 (1H, d (br)), 4.20 (1H, dd), 1.99 (1H, m), 1.39 (9H, s), 0.90 (6H, m).
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[CH3:20].C([O-])(C)(C)C.[K+]>CS(C)=O>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: Cc1cc(N)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2c(C)cccc2[N+](=O)[O-])ccc1Br

Procedure:
The product (3.90 g) is obtained according to the method of stage 1 of Example 4, by using 2.78 g of 2-fluoro-3-methyl-nitrobenzene and 5 g of 4-bromo-3-methyl-aniline in the presence of 3.22 g of potassium tert-butanolate in 70 mL of DMSO.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C@@H:31]([N:33]2[CH2:38][CH2:37][C@H:36]([OH:39])[C@@H:35]([CH3:40])[CH2:34]2)[CH3:32])[CH2:26][CH2:25]1>>[OH:39][C@H:36]1[CH2:37][CH2:38][N:33]([C@@H:31]([CH3:32])[CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:29][CH2:28]2)[CH2:34][C@@H:35]1[CH3:40]
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: C[C@H]1CN([C@@H](C)CN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN([C@@H](C)CN2CCC(NC(=O)c3cc4c(OCc5ccoc5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36) and amine 56.
Reaction SMILES: N=C=N.[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:20]=[C:21]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1)[CH2:22][CH2:23][C:24](O)=[O:25].C(Cl)Cl.CCO>C(Cl)Cl.CN(C=O)C>[O:25]=[C:24]([N:11]1[CH2:12][CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:23][CH2:22][C:21]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=1)=[O:20]
Reactant: O=C(O)CCC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(CCC(=O)N1CCc2ccccc2C1c1ccccc1)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
1.98 g (˜2.0 mmol) of PS carbodiimide resin were added to a solution of 209 mg (1.0 mmol) of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 275 mg (1.0 mmol) of 4-oxo-4-(3-(trifluoromethyl)benzylamino)butyric acid (intermediate VVV01) in a mixture of DCM and DMF (82 ml, 40:1 vv) and the mixture was shaken for 16 h at RT. Then the resin was filtered off and it was washed with DCM and MeOH. The filtrate was concentrated to small volume under vacuum. Column chromatography (DCM/EtOH 40:1) of the residue produced 287 mg (0.6 mmol, 62%) of 4-oxo-4-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(3-(trifluoromethyl)benzyl)butyric acid amide. MS: m/z 467.2 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Br.[C:7]([C:15]1[N:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][N:20]([N:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: CNn1cccc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C(=O)CBr)n1cccc1C(=O)c1ccccc1
Yield: 81.5 %

Procedure:
A solution of bromoacetyl bromide (8.47 g, 42 mmol) in 30 ml of dichloromethane was added over 30 minutes to a stirred slurry containing 2-benzoyl-1-methylaminopyrrole hydrobromide (14.9 g, 54.7 mmol) and sodium bicarbonate (5.9 g, 71 mmol) in 150 ml of dichloromethane. After 22 hours at room temperature the mixture was quenched with 150 ml of crushed ice and the layers were separated. The organic layer was washed with water, dried over anhydrous MgSO4, filtered and evaporated. The residual oil was flash chromatographed (silica gel, 5% hexane-ethyl acetate) to give 11.0 g (98%) of crystals, m.p. 76°-78°. A 2.2 g portion of this material was recrystallized from ether-hexane to afford 2.1 g of cubes, m.p. 76°-78°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:18][CH3:19])([CH3:17])[C:13](=[O:16])[NH:14][N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1C=CC(S(O[CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:18][CH3:19])([CH3:17])[C:13](=[O:16])[N:14]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC1(C)C(=O)NN=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
Prepared analogous as described for the example B1 (Alternative 1) using 5-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-2,4-dihydro-3H-pyrazol-3-one (compound C9) and tert-butyl 4-(Toluene-4-sulfonyloxy)piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B9*HCl)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:13][CH3:14].C([Li])CCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1.CCCCCC.O>[CH2:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][O:10][CH2:11][CH3:12])=[CH:7][C:2]=1[B:20]([OH:25])[OH:21])[CH3:14]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOCOc1ccc(CC)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCOCOc1ccc(CC)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
12 g (49 mmol) of 1-bromo-2-ethyl-5-ethoxymethoxybenzene are placed in 200 ml of dry THF in a round-bottomed flask and under a stream of nitrogen. The reaction medium is cooled to −78° C. and 23 ml (58 mmol) of 2.5M n-butyllithium in hexane are added dropwise. 20 minutes later, 13.6 ml (59 mmol) of triisopropyl borate are added slowly. Stirring is continued for 1 hour at −78° C. The mixture is then poured into a solution of water and hydrochloric acid and is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (50/50). After evaporating off the solvents, 6.7 g (65%) of the expected product are obtained in the form of white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:31](/[CH:32]=[CH:33]/[CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:31]([CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:13]3[CH:14]=[C:15]([C:18]([N:20]([CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:16]=[CH:17][N:12]3[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2nn3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3c2/C=C/CN2CCCCC2)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccn2nc(-c3ccc(C(C)O)cc3)c(CCCN3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(E)-2-(4-acetylphenyl)-N,N-diisopentyl-3-(3-(piperidin-1-yl)prop-1-en-1-yl)pyrazolo[1,5-a]pyridine-5-carboxamide (80 mg, 0.15 mmol) was dissolved in MeOH (3 mL) and triethylamine (1 mL) and 10% Pd/C (40 mg) was added. The vessel was flushed with 3 cycles of vacuum then hydrogen from a balloon, and the reaction mixture was stirred for 4 h at room temperature, filtered through Celite and evaporated. The residue was purified by preparative HPLC on a reverse-phase Zorbax SB-C18 column 21.2×100 mm eluted with MeOH-water-0.1% TFA. Isocratic 30% for 3 minutes then Gradient 30% to 100% MeOH over 14 minutes. LCMS m/z 547.4 (weak) (M+H)+, 458.3 (strong). ret. time=2.35 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(C)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(C)c(I)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone (20 g, 110 mmol) in acetic acid (200 mL) was added N-iodosuccinimide (29 g, 130 mmol) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, neutralized with saturated sodium bicarbonate, filtered off insoluble succinimide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was recrystallized from a mixture of ethyl acetate and hexane (25.8 mg, 77%). LCMS calculated for C9H9ClIO2 (M+H)+: m/z=311.0. found: 311.0.
Reaction SMILES: C[N:2]([CH3:17])/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:18][C:19]1[NH:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:20]=1C#N>CC(O)=O>[C:19]([C:20]1[C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)=[N:22][N:23]2[C:5]([C:7]3[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:18]
Reactant: CC(=O)Nc1cccc(C(=O)/C=C/N(C)C)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2ccnc3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn23)c1
Temperature: 118 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide (46 mg, 0.2 mmol) in HOAc (5 mL) was added 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (55 mg, 0.2 mmol). The mixture was stirred at 118° C. for 4 hr. Then the reaction mixture was concentrated to a residue and partitioned between ethyl acetate (100 mL) and brine (100 mL). Organic layer was separated, washed with brine (2×100 mL), dried over sodium sulfate and concentrated to afford 80 mg (90%) of N-(3-(3-cyano-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide as a colorless oil. MS (ESI) m/e [M+1]+ 446.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[C:21](OC)([CH3:23])[CH3:22]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH:15]([CH2:16][OH:17])[O:18][C:21]2([CH3:23])[CH3:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(C)(C)OC
Reactant: COc1ccc(CCNCC(O)CO)cc1OC
Solvent: CC(C)=O
Product: COc1ccc(CCN2CC(CO)OC2(C)C)cc1OC
Temperature: 25 °C

Procedure:
A suspension of 3-[2-(3,4-dimethoxyphenyl)ethylamino]-1,2-propanediol (13 g) and 2,2-dimethoxypropane (30 ml) in acetone (400 ml) was stirred at room temperature until a clear solution was obtained (about 24 hours). Evaporation of the solvent gave 15 g of 3-[2-(3,4-dimethoxyphenyl)ethyl]-2,2-dimethyl-5-hydroxymethyloxazolidine, as an oily residue. This residue was dissolved in acetonitrile (500 ml) and to the stirred and ice-cold solution, 3-chloro-6-triphenylmethylazopyridazine (16 g) and sodium hydrice (4 g, as a 50% suspension in oil) were added. Stirring was continued for one hour at room temperature, then 20% hydrochloric acid (20 ml) and brine (200 ml) were added, and the mixture stirred for one hour. The organic layer was separated and evaporated to dryness.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J35) (347 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K23) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown oil (340 mg, 61%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])([OH:30])[C:12]#[C:13][C:14]#[C:15][C:16]([CH3:29])([OH:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:3]>[Ni].C(O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])([OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:29])([OH:28])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH3:1]
Reactant: CC(C)CCCC(C)CCCC(C)(O)C#CC#CC(C)(O)CCCC(C)CCCC(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)(O)CCCCC(C)(O)CCCC(C)CCCC(C)C

Procedure:
In a 100 ml autoclave were placed 10 g of 2,6,10,15,19,23-hexamethyltetracosa-11,13-diyne-10,15-diol, 20 ml of ethyl alcohol and 1 g of W-5 type Raney nickel and the mixture was hydrogenated at 100° C under a hydrogen pressure of 50 ~ 60 kg/cm2 for 18 hours to give 2,6,10,15,19,23-hexamethyltetracosane-10,15-diol. The catalyst was filtered off and 1 g of Ni-catalyst supported on diatomaceous earth and 1 g of activated alumina were added to the filtrate, and it was hydrogenated at 200° C under a hydrogen pressure of 100 kg/cm2 for three days to give 7.7 g of squalane.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=O)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[CH2:19]([N:26]1[CH2:30][CH2:29][CH:28]([C:31]([N:14]([CH2:13][C:4]2[CH:3]=[CH:2][C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:33])[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)C1CCN(Cc2ccccc2)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1ccc2c(c1)OCCCO2)C(=O)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above amine product, N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (807 mg, 3 mmole) was combined with 1-Benzyl-pyrrolidine-3-carboxylic acid (615 mg, 3 mmole) in 50 ml dichloromethane. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (764 mg, 4 mmole) and dimethyl aminopyridine (562 mg, 4 mmole) were added. The reaction solution was stirred at room temperature overnight. 50 ml of water was added and the mixture was extracted with 50 ml ethyl acetate three times. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography using 50-75% ethyl acetate in hexane. MS (m+1)=457.3; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 2.00 (m, 1H), 2.05 (m, 1H), 2.15 (m, 1H), 2.25 (m, 1H), 2.55 (m, 1H), 2.65 (m, 1H), 2.90 (m, 1H), 3.00 (m, 1H), 3.10 (d, 1H), 3.15 (m, 1H), 3.25 (d, 1H), 3.40 (m, 1H), 3.75 (m, 2H), 4.30 (m, 4H), 4.45 (s, 1H), 4.55 (d, 1H), 6.6-7.0 (m, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23]Br)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:10]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH2:23][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](CCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@H]1CC[C@H](CCCOc2ccc(C=O)cc2)CC1
Yield: 121.9 %

Procedure:
1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 3-(trans-4-pentylcyclohexyl)-1-propyl bromide 8.3 g of potassium carbonate and 50 ml of butanone were reacted in an analogous manner to Example 1 to give 6.0 g of 4-[3-(trans-4-pentylcyclohexyl)-1-propyloxy]benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: CC1(C)CC(c2cccc(N3CCN(c4ccccc4F)CC3)c2)Nc2c(C(=O)O)cc(F)cc21
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCN(c4ccccc4F)CC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(F)cc21
Yield: 29.8 %

Procedure:
A mixture of 6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl)-methanesulfonamide (34.7 mg, 30%) as a light yellow solid: MS (ESI) M+1=555.3.