Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[C:20]([NH2:26])=[CH:21][CH:22]=[C:23]([F:25])[CH:24]=2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[NH:26][C:7]([C:6]2[C:2]([I:1])=[N:3][N:4]([CH3:10])[CH:5]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Cn1cc(C(=O)O)c(I)n1
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(Cl)c2)c(I)n1
Yield: 56.5 %

Procedure:
At room temperature, 273 mg (1.0 mmol) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid, 213 mg (0.83 mmol) of 3′,4′-dichloro-5-fluorobiphenyl-2-amine, 0.3 ml (1.67 mmol) of N,N-diisopropyl-ethylamine and 583 mg (1.25 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate were stirred in 5 ml of methylene chloride for 3 days. The mixture was washed with saturated sodium bicarbonate solution and then with water. Removal and concentration of the organic phase gave 910 mg of crude product. Purification by column chromatography on silica gel 60 using methylene chloride/diethyl ether 5:1 gave 230 mg (53.5% of theory) of N-(3′,4′-dichloro-5-fluoro-1,1′-biphenyl-2-yl)-3-iodo-1-methyl-1H-pyrazole-4-carboxamide (compound No. 6 from table 1) of log P (pH 2.3)=3.42.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([NH:24][C:3]([C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:6]=2)=[O:4])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NN2CCOCC2)on1
Yield: 71.6 %

Procedure:
As described for example 18, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.33 mmol) was converted, using 4-aminomorpholine (136 mg, 1.3 mmol) instead of N,N-dimethylhydrazine, to the title compound (91 mg, 71%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=9:1 to 7:3). MS: m/e=386.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:13]([C:12]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:11]=3[Cl:10])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: Nc1cc(Br)cnc1N
Product: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 2-chloro-4-hydroxybenzaldehyde.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:20][CH2:19][NH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:10]([C@@H:17]1[CH2:22][C@@H:21]([N:23]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([F:27])([F:28])[F:26])[CH2:20][CH2:19][N:18]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=CCc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(CCc2ccccc2)[C@H](Cc2ccccc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
209 μl (0.936 mmol) of phenylacetaldehyde are added dropwise over the course of 10 minutes to a solution of 100 mg (0.233 retool) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine, 58 mg (0.702 mmol) of sodium acetate, 44 mg (0.702 mmol) of sodium cyanoborohydride and 67 μl (1.17 mmol) of acetic acid in 2 ml of ethanol at room temperature. The reaction mixture is left to stir at room temperature for 16 hours. The residue after evaporation in a rotary evaporator is taken up in ethyl acetate, and the organic phase is washed with water and with brine, dried over magnesium sulfate and evaporated to dryness. The yellow oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (2000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (2000:50:1) Rf =0.33, FD-MS: M+ =531.
Reaction SMILES: [C:1](N1C=CN=C1)#[N:2].[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2.O>CN(C)C(=O)C>[F:41][C:9]([F:8])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:13][N:14]([C:1]#[N:2])[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:16]1=2
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Reactant: N#Cn1ccnc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(Br)ccc21
Temperature: 100 °C

Procedure:
Add a solution of 1-cyanoimidazole in N,N-dimethylacetamide to a solution of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate in N,N-dimethylacetamide at room temperature under nitrogen and heat the mixture to 100° C. Pour the cooled mixture into water and extract with methylene chloride. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Chromatograph the residue over silica gel to afford the title compound.
Reaction SMILES: Br[CH2:2][B-:3]([F:6])([F:5])[F:4].[K+:7].[C:8]([N:15]1[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:11]([O:10][C:8]([N:15]1[CH2:20][CH2:19][N:18]([CH2:2][B-:3]([F:6])([F:5])[F:4])[C@H:17]([CH3:21])[CH2:16]1)=[O:9])([CH3:14])([CH3:12])[CH3:13].[K+:7]
Reactant: F[B-](F)(F)CBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A mixture of potassium (bromomethyl)trifluoroborate (1.20 g, 5.38 mmol) and (R)-4-N-Boc-2-methyl-piperazine (1.166 g, 5.65 mmol) in THF (7.00 mL) was heated at 80° C. under nitrogen for 24 h. After cooling, the mixture was concentrated, re-dissolved in acetone (125 mL) and treated with K2CO3 (1 eq). The suspension was stirred for 30 min and filtered through a short plug of Celite® (diatomaceous earth), washing with additional acetone and the combined organic phases were concentrated to give potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate as a pale yellow foam (1.627 g, 94%). 19F-NMR (377 MHz, d6-acetone) δ −141.36.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[N:9]1([CH2:14][CH:15]([N:17]2[C:30]3[CH:29]=[C:28]([C:31](=S)N)[CH:27]=[CH:26][C:25]=3[S:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:30]=2[CH:29]=1
Reactant: NC1CCCCC1N
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C
Yield: 30.9 %

Procedure:
1,2-Diaminocyclohexane (9.12 g) is added to an ethanolic solution (32 cc) of 10-[(2RS)-1-(pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.96 g). The mixture is heated in an autoclave to 150° C. for 10 hours. The reaction mixture is diluted with ethyl acetate (150 cc) and washed with distilled water (4×100 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 23 cm; diameter: 2.5 cm) of FLUKA type 507 C neutral alumina, eluting with 50:50 (by volume) mixtures (1 liter) of cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 2 to 15 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-[(2RS)-1-(pyrrolidinyl)-2-propyl]phenothiazine (1.07 g) in the form of a brown product of meringue-like consistency.
Reaction SMILES: [OH:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:20]([O:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1(O)CCc2c(OC)ccc(OC)c2C1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(OC(C)=O)CCc2c(OC)ccc(OC)c2C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
5.0 g of methyl rac-1,2,3,4-tetrahydro-2-hydroxy-5,8-dimethoxynaphthalene-2-carboxylate were dissolved in 50 ml of pyridine. The solution was cooled to 0° C. and 10 ml of acetic anhydride and 150 mg of 4-dimethylaminopyridine were added. After standing at 0° C. for 24 hours, the mixture was poured into 250 ml of water. The mixture obtained was extracted with three 100 ml portions of ethyl acetate and the combined ethyl acetate extracts were washed with 2-N hydrochloric acid until the washings were acidic, then with 200 ml of water, 200 ml of dilute aqueous potassium hydrogen carbonate and 200 ml of brine. After drying, the solvent was evaporated to give a white crystalline residue. Recrystallisation from diethyl ether gave 5.6 g (96.5%) of methyl rac-2-acetoxy-1,2,3,4-tetrahydro-5,8-dimethoxynaphthalene-2-carboxylate in the form of colourless crystals of melting point 155.5°-156° C.
Reaction SMILES: C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=O)=[CH:15][CH:14]=2)[N:8]=1)CCCCC.[CH2:22](Cl)[CH2:23]Cl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:9]([C:12]1[CH:11]=[N:10][C:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]#[N:19])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)[CH2:13][CH2:14][CH2:15][CH2:22][CH3:23]
Reactant: CCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1
Reactant: ClCCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCc1cnc(-c2ccc(C#N)cc2)nc1

Procedure:
15.58 g. of 4-(4-n-hexylpyrimid-2-yl)benzoic acid amide are left in a mixture of 350 ml. of ethylene chloride and 5.58 ml. of phosphorus oxychloride for 90 minutes under reflux, with stirring. The reaction mixture, diluted with ether, is washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, drying over sodium sulfate, 14.6 g. of 5-n-hexyl-2-(4-cyanophenyl)pyrimidine result, which are distilled in high vacuum, m.p. 53.5° - 54.5°; cl.p. 35.5° - 36.5°.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]([C:13]1[C:18]([NH:19][OH:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>O>[OH:20][N:19]([C:18]1[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2](=[O:3])[O:4][CH3:5]
Reactant: COC(=O)Cl
Reactant: ONc1cccnc1Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N(O)c1cccnc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g (mmol) of methyl chloroformate were added dropwise at 0° C. to a mixture of 7.8 g (39 mmol) of N-(2-phenoxypyridin-3-yl)hydroxylamine (Example 1.b), 4 g (50 mmol) of NaHCO3 (solid) and 10 ml of methylene chloride. After 1 hour at room temperature (approximately 25° C.), the reaction mixture was treated with a further 2 g of methyl chloroformate and stirred for a further 2 hours at room temperature. The reaction mixture was subsequently treated with a further 2 g of methyl chloroformate and left for approximately 12 hours at 5° C. The resulting mixture was treated with water and extracted repeatedly using tert-butyl methyl ether. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The residue obtained was purified by column chromatography (cyclohexane/ethyl acetate). This gave 2.5 g of the title compound as a solid (m.p.: 140° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:8]([NH:1][C@H:2]([C:3]([NH2:5])=[O:4])[C:6]#[N:7])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC(N)C(N)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: N#C[C@H](NC(=O)c1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-2-cyanacetamide (8 g, 0.08 mol) in pyridine (10 mL) is added a solution of benzoyl chloride (0.08 mol) in pyridine (15 mL) and the mixture is stirred at rt for 40 min. It is then concentrated under reduced pressure to provide crude product which is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13](OCC)=[O:14])[CH:11]=[CH:12][C:6]=2[O:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(Cl)Cl>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:8][C:7]=2[CH:9]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(COC)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCC1Cc2cc(CO)ccc2O1
Yield: 64 %

Procedure:
To an anhydrous solution of 2.66 g (11.26 mmole) ethyl 2-methoxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 15 ml tetrahydrofuran was added, in portions with stirring under nitrogen, 426 mg (11.26 mmole) lithium aluminum hydride and the mixture was stirred at room temperature for 2.4 hours. The reaction was quenched by cautious, dropwise addition of water, then acidified with 1N hydrochloric acid. The volatiles were evaporated and the residue taken up in water and extracted with ethyl ether, washing the extracts with brine. After drying over anhydrous magnesium sulfate and evaporation of solvent 1.674 g of oil was obtained. This crude product was dissolved in a small amount of methylene chloride and purified by column chromatography on silica gel to afford 1.40 g of product which was used as starting material in the procedure of Example 5.
Reaction SMILES: [H][H].[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH:54]=[CH2:55])[CH:48]([O:56][CH2:57][CH:58]=[CH2:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]>[Rh]>[CH2:3]([CH:5]1[CH:31]=[C:30]([CH3:32])[CH2:29][CH:28]([CH3:33])[CH2:27][CH:26]([O:34][CH3:35])[CH:25]2[O:36][C:21]([OH:40])([CH:22]([CH3:39])[CH2:23][CH:24]2[O:37][CH3:38])[C:20](=[O:41])[C:19](=[O:42])[N:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[C:12](=[O:43])[O:11][CH:10]([C:44]([CH3:60])=[CH:45][CH:46]2[CH2:51][CH2:50][CH:49]([O:52][CH2:53][CH2:54][CH3:55])[CH:48]([O:56][CH2:57][CH2:58][CH3:59])[CH2:47]2)[CH:9]([CH3:61])[CH2:8][CH2:7][C:6]1=[O:62])[CH3:4]
Reactant: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCC=C
Reactant: [H][H]
Agent: [Rh]
Product: CCCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OCCC
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 65.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-diallyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (6.8 mg in 600 μl ethyl acetate) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 25 minutes, the mixture was filtered over Celite, concentrated and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:3)+1% methanol) to give the title compound (4.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH:22]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:26]([CH:22]4[CH2:25][CH2:24][CH2:23]4)=[O:27])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCC1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)C2CCC2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)cyclobutanecarboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and cyclobutanecarboxylic acid using method D. NMR; δH [2H6]—DMSO 9.71,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.52-7.49,(2H, m), 7.40,(2H, d), 7.21,(1H, d), 3.21-3.14,(3H, m), 2.24-2.15,(5H, m), 2.07,(2H, m), 1.91, (1H, m), 1.78,(1H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.30 min, MH+363.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[N:2]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([O:10][CH:11]2[CH2:16][CH2:15][CH:14]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:13][CH2:12]2)=[N:2]1
Reactant: O=C1CCC(Oc2noc3ccccc23)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3noc4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(benzo[d]isoxazol-3-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:19][CH3:20])[C:12]2[CH2:18][NH:17][CH2:16][CH2:15][C:13]=2[N:14]=1.[CH3:21][CH:22]([CH3:30])[C:23](=[O:29])[CH2:24][C:25](OC)=[O:26]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[C:9]1[N:10]=[C:11]([O:19][CH3:20])[C:12]2[CH2:18][N:17]([C:25](=[O:26])[CH2:24][C:23](=[O:29])[CH:22]([CH3:30])[CH3:21])[CH2:16][CH2:15][C:13]=2[N:14]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: COc1nc(-c2c(C)cccc2C)nc2c1CNCC2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COc1nc(-c2c(C)cccc2C)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (4.8 g, 17.82 mmol), methyl 4-methyl-3-oxopentanoate (5.14 g, 35.6 mmol), and DMAP (0.327 g, 2.67 mmol) was dissolved in toluene (70 mL). The mixture was evenly divided into four 20 mL microwave vials. Each vial was heated to 150° C. for 30 min via microwave irradiation. The reaction mixtures were combine and directly concentrated. The resulting residue was purified via silica gel FCC (0-80% EtOAc/heptane) to give 1-(2-(2,6-dimethylphenyl)-4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione. MS (ESI+) m/z 382.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCCl)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 6-chloro-1-phenyl-1-hexanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: Anal. Calcd for C27H36N2O2+0.1CHCl3: C, 75.3; H, 8.39; N, 6.46. Found: C, 75.4; H, 7.89; N, 6.18; ESMS m/e: 421.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: Cc1cccc(N2CCNCC2)n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methyl-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:23][NH:22][CH2:21][CH2:20][NH:19]2)=[CH:14][CH:13]=1>O1CCCC1>[CH2:1]([N:19]1[CH2:20][CH2:21][N:22]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][C@@H:18]1[C:15]1[CH:14]=[CH:13][C:12]([Br:11])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc([C@H]2CNCCN2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
Hydrogen chloride in ethyl acetate solution (4N) was added to a solution of di-tert-butyl (2S)-2-(4-bromophenyl)piperazine-1,4-dicarboxylate (10 g, 22.7 mmol) in methanol (50 ml). The mixture was stirred for one hour at room temperature and the solvent was evaporated under reduced pressure to give white solid. The mixture was partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford (2S)-2-(4-bromophenyl)piperazine as white crystals. Benzylbromide (9.7 g, 56.7 mmol) was added to a solution of sodium hydride (60% in oil, 2.0 g, 50 mmol) and (2S)-2-(4-bromophenyl)piperazine in tetrahydrofuran (50 ml) at room temperature and the mixture was stirred for one hour. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish (2S)-1,4-Dibenzyl-2-(4-bromophenyl)piperazine (6.1 g, 64%) as a colorless oil.