Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][S:17]([C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:21])[F:22])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:3][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(N[C@H]1CC[C@H](O)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.9, trans-4-amino-cyclohexanol and 4-(trifluoromethyl)-benzenesulfonyl chloride were converted to yield trans-N-(4-Hydroxy-cyclohexyl)-4-trifluoromethyl-benzenesulfonamide as white solid, 176.2° C., MS 322 (M-H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.BrC1C=CC=C2C=1C=CN=C2.[ClH:23].BrC1C=C2C(=CC=1)C=[N+]([O-:35])C=C2.Cl.BrC1C=CC=C2C=1C=C[N+]([O-])=C2>>[ClH:23].[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:35])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccncc2c1
Reactant: [O-][n+]1ccc2cc(Br)ccc2c1
Agent: Brc1cccc2cnccc12
Agent: Cl
Agent: [O-][n+]1ccc2c(Br)cccc2c1
Product: [O-][n+]1ccc2ccc(Br)cc2c1

Procedure:
Compound 37a was prepared from 7-bromoisoquinoline (Tyson, F. L., J. Am. Chem. Soc. 61, 183 (1939), this procedure gave a mixture of 7-bromoisoquinoline and 5-bromoisoquinoline) using the procedure described for 1a. The title compound was contaminated with the 5-bromoisoquinoline N-oxide hydrochloride. M.p. 107.0-112.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:10]=2[O:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:30][CH:31]1[NH:33][CH2:32]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.O>[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:10]=2[O:11][CH2:12][C:13]([N:33]2[CH2:32][CH:31]2[CH3:30])=[O:15])=[CH:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)O)c1
Reactant: CC1CN1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OCC(=O)N2CC2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid obtained in Reference Example 157 (9.00 g, 28.8 mmol) in THF (90 mL) was added dropwise oxalylchloride (3.77 mL, 43.2 mmol) with ice-cooling, and was then added DMF (four drops), and then the mixture was stirred for 30 minutes. The reaction solution was stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. To a solution of propyleneimine (1.97 g, 34.6 mmol) and triethylamine (4.82 mL, 34.6 mmol) in THF (80 mL) was added dropwise the obtained solution of acid chloride in THF (100 mL) with ice-cooling. The mixture was stirred for 30 minutes, and then was warmed to room temperature, and water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 10.0 g (yield 99%) of the title compound. Oily matter.
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8](=[N:10][OH:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.Cl>C(O)(=O)C>[CH3:9][C:8]1[N+:10]([O-:11])=[C:21]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[O:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=NO)C(=O)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(-c2oc(-c3ccccc3)c(C)[n+]2[O-])cc1

Procedure:
12.5 g of 1-phenyl-1,2-propanedione-2-oxime and 10 ml of p-tolualdehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced for 30 minutes, with ice-cooling. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in water and the pH is made alkaline using ammonia. The mixture is extracted three times with in each case 200 ml of dichloromethane, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 6.4 g of 4-methyl-5-phenyl-2-p-tolyloxazole 3-oxide as a white solid. C17H15NO2 (265.31), MS (ESI)=266 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:47]=[CH:46][C:12]([CH2:13][C@H:14]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]([C:34]3[C:42]4[CH:41]=[N:40][CH:39]=[N:38][C:37]=4[N:36]([CH:43]([CH3:45])[CH3:44])[CH:35]=3)=[O:33])[CH:31]=2)=[O:24])[NH:15]C(OC(C)(C)C)=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@H:14]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([C:32]([C:34]3[C:42]4[CH:41]=[N:40][CH:39]=[N:38][C:37]=4[N:36]([CH:43]([CH3:44])[CH3:45])[CH:35]=3)=[O:33])[CH:31]=2)=[O:24])[NH2:15])=[CH:46][CH:47]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(NC(=O)[C@@H](Cc3ccc(C(=O)c4ccccc4)cc3)NC(=O)OC(C)(C)C)c2)c2cncnc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)[C@H](N)Cc3ccc(C(=O)c4ccccc4)cc3)c2)c2cncnc21
Yield: 56 %

Procedure:
4-benzoyl-Nalpha-(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-D-phenylalaninamide (Example 284, 20 mg, 0.03 mmol) was stirred with 10% hydrochloric acid in 1,4-dioxane (5 mL) at room temperature for 1 hour. The mixture was evaporated in vacuo and purified by preparative HPLC to afford the title compound as a gum in 56% yield, 9 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])[CH2:12]3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:14][C@H:13]3[C@@H:9]2[CH2:10][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])[CH2:12]3)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)N1C[C@@H]2C[C@@H](c3ccc(Cl)cc3)[C@@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)N1C[C@H]2C[C@H](c3ccc(Cl)cc3)[C@H]2C1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of Example 48A (0.44 g, 1.4 mmol) in methanol (4 mL) and water (4 mL) was added 5 N aqueous NaOH solution (1.4 mL, 7.1 mmol). After stirring at 60° C. for 16 hours, the reaction mixture was cooled, neutralized to pH˜7 with 3 N HCl, and concentrated to obtain crude 2-[(1S,5R,6S)-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]hept-3-yl]-2-methylpropanoic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: COc1ncccc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-2-methoxypyridine (293 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (315 mg, 59%) as a light yellow oily substance.
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:15]([OH:17])=O)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:2][C:1]([NH:5][C:6]1[O:7][C:8]([C:15]([Cl:20])=[O:17])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1

Procedure:
By the procedure of Example 27, 17 g (64.5 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarboxylic acid, 67 ml thionyl chloride and 4 of drops dimethylformamide were reacted together. The product was separated and then distilled to yield 17.2 g of a yellow solid product (m.p.=52°-60° C.; b.p. 70° C. @ 0.25 mm Hg) identified in Table I.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](=[CH:14][CH2:15][OH:16])[C:11](O)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10](=[CH:14][CH2:15][OH:16])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(=CCO)C(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(=CCO)CO
Temperature: -78 °C
Reaction time: 4 h

Procedure:
A 2. 210 g (9.69 mmol) sample of 3-((t-butyldimethylsilyloxy)methyl-4-hydroxybut-2-eneoic acid, 1,4lactone, from Example 336A, was dissolved in 6 mL of methylene chloride, cooled in a dry ice bath, and 14.2 mL (21.3 mmol) of DIBAL was added. The mixture was stirred at -78° C. for 4 hours, allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to -78° C. and quenched with 1.53 mL of methanol and 2.55 mL of water. The mixture was filtered, and the filtrate concentrated and chromatographed on silica gel, eluting with 50% and 90% ethyl acetate in hexane. The solvent was removed and the product dried to afford 1.055 g of the title product, which was taken directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O>[F:22][CH:23]([F:33])[O:24][C:25]1[CH:26]=[C:27]([C:28]2[NH:1][C:2]3=[N:7][C:6]([N:8]4[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:9]4)=[CH:5][CH:4]=[C:3]3[N:19]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1cccc(OC(F)F)c1
Reactant: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(OC(F)F)c4)[nH]c3n2)C1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Into a 4 mL vial was added (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide (500 μL, 0.3M) dissolved in N,N-dimethylformamide followed by 3-(difluoromethoxy)benzaldehyde (950 μL, 0.158M) dissolved in N,N-dimethylformamide. Water (50 μL) was added followed by sodium hydrosulfite (574 μmol) under a nitrogen atmosphere. The vial was capped and shaken at 110° C. for 18 h. The solvent was removed by Speedvac and the residue was purified by HPLC to afford the title compound. MS (API-ES+) (M+H) 416.2; HPLC retention time 1.392 min (Method E).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[N:27]([CH3:28])[CH:26]=[CH:25][C:19]3=[N:20][C:21]=2[C@@H:22]([NH2:24])[CH3:23])[CH:13]=[CH:12][N:11]=1)C1C=CC=CC=1.Cl.N[C@H](C1N=C2C=CN(C)C2=CC=1C1C=CN=C(O)C=1)C.[NH2:50][C:51]1[N:56]=[C:55]([NH2:57])[C:54]([C:58]#[N:59])=[C:53](Cl)[N:52]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:50][C:51]1[N:56]=[C:55]([NH2:57])[C:54]([C:58]#[N:59])=[C:53]([NH:24][C@H:22]([C:21]2[N:20]=[C:19]3[CH:25]=[CH:26][N:27]([CH3:28])[C:18]3=[CH:17][C:16]=2[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([OH:9])[CH:15]=2)[CH3:23])[N:52]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnc(OCc2ccccc2)c1
Agent: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnc(O)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccnc(O)c1
Temperature: 120 °C
Yield: 46.3 %

Procedure:
A mixture of (S)-1-(6-(2-(benzyloxy)pyridin-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (155 mg, 0.393 mmol) and (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)pyridin-2-ol hydrochloride (120 mg, 0.393 mmol) along with 2,4-diamino-6-chloropyrimidine-5-carbonitrile (100 mg, 0.590 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.205 mL, 1.18 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was dissolved in MeOH (10 mL). Pd/C (10%, 700 mg) was added and the reaction mixture was maintained under an atmosphere of hydrogen for 30 minutes. The mixture was filtered through Celite and concentrated. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 20-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound (73 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.22-1.32 (m, 3 H), 3.80 (br s, 3 H), 5.58 (quin, J=6.71 Hz, 1 H), 6.31 (d, J=6.83 Hz, 1 H), 6.48 (br s, 2 H), 6.52-6.63 (m, 5 H), 6.66 (d, J=7.81 Hz, 1 H), 7.52 (d, J=6.35 Hz, 1 H), 7.72 (d, J=2.93 Hz, 1 H), 7.80 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H19N9O, 402; found 402.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28]([N:33]=[N+:34]=[N-:35])[N:27]=[CH:26][N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(Oc3cc(Cl)ncn3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1

Procedure:
A solution of 300 mg (0.65 mMol) of 7-(6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide and 84 mg (1.3 mMol) NaN3 in 3.8 ml DMF is stirred at 60° C. for 90 min. Then the solution is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=470; HPLC: AtRet=16.9.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([N:24]2[CH2:25][CH2:26][N:27]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:28][CH2:29]2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: C1CCC(N2CCNCC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(C4CCCC4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 36.2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.303 g, 1.25 mmol) and 1-cyclopentyl piperazine (0.198 g, 1.28 mmol) in methanol (11 mL) and stir. After 15.5 h, add sodium borohydride (0.109 g, 2.88 mmol), and stir at ambient temperature. After 1 h, concentrate the reaction mixture and purify by silica gel chromatography (ethyl acetate→4:1 ethyl acetate:methanol) to provide 0.172 g (36%) of the title compound as an off white solid: high resolution mass spectrum (electrospray): m/z calc for C22H29N4O2 381.2291, found 381.2306; 1H NMR (DMSO-d6): 8.66 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 2H), 7.04 (d, 1H, J=7.8 Hz), 3.61 (s, 2H), 3.00-2.25 (m, 9H), 2.01-1.88 (m, 2H), 1.82-1.69 (m, 2H), 1.69-1.56 (m, 2H), 1.53-1.38 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cccc(C(F)(F)F)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.184 g (0.307 mmol) of (2R*,4S*)-2-benzyl-1-(3-trifluoromethylbenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.046 g (1.23 mmol) of sodium borohydride in analogy to Example 2. The title compound of the formula ##STR29## is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.28, FD-MS: M+ =503.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][C:14]([F:18])([F:17])[C@@H:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[C:29]([CH3:30])=[C:28]2[C:23]([C:24](=[O:40])[C:25]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:26][N:27]2[C@@H:31]2[CH2:33][C@@H:32]2[F:34])=[CH:22][C:21]=1[F:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][C:14]([F:18])([F:17])[C@@H:13]1[CH2:12][N:11]([C:20]1[C:29]([CH3:30])=[C:28]3[C:23]([C:24](=[O:40])[C:25]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:26][N:27]3[C@@H:31]3[CH2:33][C@@H:32]3[F:34])=[CH:22][C:21]=1[F:41])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@]12CCC(F)(F)[C@@H]1CNC2
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(Br)c(F)cc2c1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(N3C[C@H]4C(F)(F)CC[C@@]4(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of (1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane (318 mg, 1.21 mmol), ethyl 7-bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (426 mg, 1.10 mmol), 1,1′-bis(diphenylphosphino)ferrocene (183 mg, 0.331 mmol), tris(dibenzylideneacetone)dipalladium(0) (101 mg, 0.110 mmol) and cesium carbonate (718 mg, 2.20 mmol) in dioxane (5.51 mL) was stirred at room temperature for 30 minutes, and at 100° C. for 11 hours under argon atmosphere. The mixture was diluted with water, and extracted with ethyl acetate and chloroform (3×). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/hexane=10:90→50:50→67:33→ethyl acetate) to afford 436 mg of the title compound as a pale yellow foam.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>ClCCl>[Si:11]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
To a cooled (0° C.) and stirred solution of 1-phenylethane-1,2-diol (1.0 g, 7.24 mmol) and tert-butyldimethylsilyl chloride (1.1 g, 7.24 mmol) in dichloromethane was added imidazole (0.74 g, 10.86 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 20 hours. The reaction mixture was washed with water, dried, and concentrated to yield 1.8 g of 2-(tert-butyldimethylsilanyloxy)-1-phenylethanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Reactant: CN1CCNCC1
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)N1CCN(C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 412 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3 H) 2.82 (s, 3 H) 4.02 (br. s., 4 H) 4.56 (br. s., 4 H) 7.79 (d, J=8.59 Hz, 2 H) 8.12 (br. s., 2 H) 8.37 (s, 1 H) 8.59 (br. s., 2 H); ESI-MS m/z (M+H)+ calc'd for C22H22N6O2, 403.18; found 403.3.
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](=O)/[C:11](/[F:16])=[CH:12]/N(C)C)=[CH:8][N:7]=[C:6]2[CH3:18])[CH2:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32]3[N:34]=[C:10]([C:9]4[N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[C:6]([CH3:18])=[N:7][CH:8]=4)[C:11]([F:16])=[CH:12][N:33]=3)=[CH:29][CH:30]=2)[CH2:20][CH2:21]1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1ncc(C(=O)/C(F)=C/N(C)C)n1C1CCC1
Product: Cc1ncc(-c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2F)n1C1CCC1

Procedure:
The title compound was prepared from (2Z)-1-(1-cyclobutyl-2-methyl-1H-imidazol-5-yl)-3-(dimethylamino)-2-fluoroprop-2-en-1-one (Method 16; 234 mg) and N-(4-morpholin-4-ylphenyl)guanidine (Method 4; 410 mg) by the procedure of Example 111 to yield a white solid (288 mg, 76%). NMR: 1.61-1.72 (m, 2H), 2.29-2.45 (m, 4H), 2.75 (s, 3H), 3.26-3.34 (m, 4H), 3.90-3.97 (m, 4H), 5.22 (quintet, 1H), 7.38-7.45 (m, 2H), 7.68 (d, 2H), 8.08 (d, 1H), 8.73 (d, 1H), 9.95 (brs, 1H); m/z 409.