Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30]>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[S:29]([C:4]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(OCC3(S(=O)(=O)c4ccc(F)cc4F)CCNCC3)cccc2n1
Yield: 99 %

Procedure:
The sulfonamide was obtained by reacting 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (50 mg; 0.18 mmol) and 2,4-difluorobenzenesulfonyl chloride (79 mg; 0.37 mmol) via Method AA to yield 80 mg. (99% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.86 (m, 1H), 7.61 (m, 1H), 7.33 (m, 2H), 7.12 (br s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.93 (br s, 2H), 3.97 (d, J=6.0 Hz, 2H), 3.71 (br d, J=12.0 Hz, 2H), 2.56 (t, J=12 Hz, 2H), 2.0 (s, 1H), 1.85 (d, J=10.4 Hz, 2H), 1.34 (m, 2H). MS m/z (ESI) 451 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N.C([O-])([O-])=O.[K+].[K+]>C(#N)CC>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: CC1CCNCC1
Agent: C[P+](C)(C)CC#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC1CCN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of ester 8 (3 g, 12.28 mmol), 4-methyl piperidine (1.46 ml, 12.28 mmol) and DIEA (2.7 ml, 15.96 mmol) in 30 ml of propionitrile is treated with solid cyanomethyl-trimethyl-phosphonium iodide (3.58 g, 14.74 mmol) and heated at reflux for 3 hours. After cooling to room temperature, a 2M-K2CO3 solution is added until basic and the mixture is extracted twice with DCM. The organic layers are washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude material is purified by chromatography using EtOAc/MeOH (saturated with ammonia): 9/1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]4[NH:39][C:38](=[O:40])[O:37][N:36]=4)=[CH:25][CH:24]=3)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]2[CH3:44])=[CH:11][CH:10]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C:2]3=[O:1])=[CH:14][CH:13]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(O[C@H]3CCCC[C@@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 15 h
Yield: 90.3 %

Procedure:
To a solution of 3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.30 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.32 g), and the mixture was stirred for 15 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.27 g, 90%).
Reaction SMILES: [C:1](#[N:16])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.[NH2:18][OH:19].[OH-].[Na+]>C(O)C>[NH2:16][C:1]1[O:19][N:18]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]=1
Reactant: NO
Reactant: CCCCCCCCCCCCC#CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cc(N)on1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.2 %

Procedure:
A solution of 2-pentadecynenitrile (10.0 g, 45.6 mmol) in ethanol (50 mL) was added to a stirred solution of hydroxylamine hydrochloride (3.8 g, 54.6 mmol) in 2.5 N NaOH (20.0 mL, 50.1 mmol). The resulting mixture was diluted with ethanol (100 mL) and stirred (22 hours, 25° C.). The obtained slurry was concentrated, then partitioned between ethyl acetate (300 mL) and brine (100 mL). The organic layer was dried (MgSO4), concentrated in vacuo, and chromatographed on silica (95:5 to 70:30 hexane:ethyl acetate) to yield 8.2 g (71.2%) of 5-amino-3-dodecyl-isoxazole as a waxy solid, m.p. 48.5°-49.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=1>O1CCCC1.CN(C)C=O>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][N:45]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(c4ccc([N+](=O)[O-])cn4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (120 mg) in a mixture of tetrahydrofuran (1.2 ml) and dimethylformamide (1.2 ml) were added triethylamine (0.068 ml) and 2-chloro-5-nitropyridine (58 mg), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=4:1) and dried under reduced pressure to give the title compound (120 mg).
Reaction SMILES: [F:1][C:2]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[N:14]([N:25]=[CH:26][C:27]=3[C:28](O)=[O:29])[C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[O:9])[CH2:4][CH2:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:11]=[N:12][C:13]3[N:14]([N:25]=[CH:26][C:27]=3[C:28]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:29])[C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[CH3:24])=[O:9])[CH2:6][CH2:7]1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccc(F)cc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(F)(c4ccc(F)cc4)CC3)cnc12
Yield: 30 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl]-7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (26 mg, 0.05 mmol) obtained in step 4 and ethanesulfonamide (27 mg, 0.26 mmol), the title compound (9 mg, 30%) was obtained.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1.[I-:15].[K+].S(=O)(O)[O-].[Na+].[OH-].[Na+]>O.CN(C=O)C.Cl>[I:15][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: Ic1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
Sodium nitrite (5.87 g, 85 mmol) in water (20 mL) was added dropwise to an ice-cooled solution of 6-aminoindazole (10 g, 75.6 mmol) in DMF (80 mL) and hydrochloric acid (6M, 40 mL) and the mixture was stirred for 30 minutes. Potassium iodide (13.5 g) was then added in small portions (gas evolution occurred) and the mixture was stirred for 1 h before warming to room temperature for 16 h. The reaction was neutralized with aqueous sodium bisulfite followed by aqueous sodium hydroxide. The mixture was filtered to remove solid, and the solid was washed first with water to remove impurities, and then with ethyl acetate and THF to collect the product. The organic washes were evaporated and recombined with the aqueous layer for extraction with ethyl acetate (3×250 mL). The organic layer was washed sequentially with water and brine, dried over sodium sulfate, and the solvent was removed in vacuo. Filtration chromatography on silica gel (35-60% ethyl acetate in hexane) yield a yellow solid, which was then triturated with 50% ethyl acetate in hexane and finally ethyl acetate to yield the product (4.96 g).
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[O:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C1COCC1.CCOC(C)=O>[CH:1]1([N:4]([CH:20]2[CH2:21][CH2:22][N:23]([CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[CH2:24][CH2:25]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(C3CCOCC3)CC2)cc1)C(F)(F)F
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.), tetrahydro-4H-pyran-4-one (65 μL, 7.0 mmol, 3.5 equiv.) and AcOH (23 μL, 0.40 mmol, 2 equiv.) in 1,2-dichloroethane/THF (2/1, 1.5 mL) was treated with NaBH(OAc)3 (210 mg, 1.00 mmol, 5.0 equiv.). After being stirred for 48 h at 75° C., the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2, gradient elution) gave the title compound as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=8.3 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 4.26-4.20 (m, 1H), 4.06-4.02 (m, 2H), 3.40-3.35 (m, 2H), 3.14-3.07 (m, 2H), 2.55-2.52 (m, 2H), 2.48 (s, br, 1H), 2.39-2.35 (m, 2H), 2.16-2.07 (m, 2H), 1.99-1.93 (m, 2H), 1.79 (s, 3H), 1.80-1.73 (m, 2H), 1.65-1.60 (m, 2H), 0.58-0.53 (m, 2H), 0.47-0.42 (m, 2H); MS(ESI) 441 [M+H]+.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:27])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:27][C@H:9]1[C@@H:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:11](=[O:13])[O:12]1
Reactant: Cc1ccc(CCOC(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CCOC(=O)N[C@H]2C(=O)O[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
In a four necked round bottom flask, Et3N (7.3 mL, 52.5 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-({[2-(4-methylphenyl)ethoxy]carbonyl}amino) butanoic acid (4.85 g, 17.5 mmol) in dry CH2Cl2 (190 mL) under argon. After cooling at 0° C., HBTU (9.87 g, 26.2 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.658 g) was further triturated with cyclohexane to afford the pure title compound (0.450 g, 10%), as white solid. MS (ESI) m/z: 262.21 [M−H]−. FTIR (cm−1): 3299, 3050, 2966, 2924, 2854, 1827, 1690, 1540, 1355, 1270, 1121, 1095, 1021, 844, 817. 1H-NMR (CDCl3): δ 1.42 (d, 3H); 2.33 (s, 3H); 2.90 (t, 2H); 4.31 (t, 2H); 4.81-4.88 (m, 1H); 5.39-5.46 (m, 2H); 7.08-7.13 (m, 4H).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:10]1([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cnccc1Br
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1cnccc1-c1ccccc1
Temperature: 110 °C
Yield: 50.5 %

Procedure:
4-bromonicotinaldehyde (150 mg, 0.81 mmol), phenylboronic acid (98 mg, 0.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (46.6 mg, 0.05 mmol) were mixed in dioxane (3.5 mL). Na2CO3 (2 M solution in water, 0.81 mL, 1.63 mmol) was added and the reaction mixture was stirred and heated in the microwave (110° C., 150 W) for 30 min. After addition of excess water followed by extraction with EtOAc, the combined organic layers were filtered (celite) and dried (MgSO4). Purification by flash chromatography (heptane/EtOAc, gradient 5-40% EtOAc) provided 4-phenylnicotinaldehyde (75 mg, 48%) as a dark yellow gum. ESI-MS [M+H]+=279.1.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9][CH:8]=[C:7]1[OH:24])=O.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>O1CCCC1>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][N:29]=[CH:1][C:3]1[C:16]([OH:17])=[C:15]([CH3:18])[C:14]([OH:19])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:20]([O:22][CH3:23])=[O:21])=[CH:9][CH:8]=[C:7]1[OH:24]
Reactant: CN(C)CCN
Reactant: COC(=O)c1ccc(O)c2nc3c(C=O)c(O)c(C)c(O)c3nc12
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c2nc3c(C=NCCN(C)C)c(O)c(C)c(O)c3nc12
Reaction time: 0.33 h

Procedure:
6-Formyl-4,7,9-trihydroxy-8-methyl-1-phenazinecarboxylic acid, methyl ester (500 mg, 1.52 mmol) was suspended in 50 ml of tetrahydrofuran and 2-(dimethylamino)ethylamine (160 mg, 1.83 mmol) was added dropwise with stirring to produce a deep purple solution. After about 20 minutes at room temperature, an orange precipitate formed and the reaction mixture gradually developed an orange color.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
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: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Temperature: 25 °C
Yield: 59 %

Procedure:
2,4-Dichloropyrimidine (1.060 g, 7115 μmol) and N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (2.86 g, 8988 μmol) were suspended in 1,4-dioxane (40 mL) to which palladium tetrakis (triphenylphosphine) (782 mg, 677 μmol) was added, followed by 2 mL of 1,4-dioxane and sodium carbonate (7.1 mL, 2.0 M in water, 14200 μmol). Argon was bubbled through the solution for about 1 minute, and the flask was fit with a reflux condensor and placed in a preheated oil bath (95 C) and heated while stirring under argon. When LCMS indicated a complete reaction, the reaction flask was cooled to RT and filtered through Celite® (diatomaceous earth). The Celite® (diatomaceous earth) pad was washed with 1,4-dioxane, and 1:1 DCM/MeOH. The filtrate was concentrated, treated with DCM, and filtered. The solid was washed with DCM, collected, and dried under vacuum to afford the desired product (1.28 g, 4.20 mmol, 95% purity, 56% yield). MS (ESI pos. ion) m/z: 305. Calculated exact mass for C13H9ClN4OS: 304.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[NH2:12])[CH2:9]2.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[C:19]([NH:12][CH:3]1[CH:4]2[CH2:5][CH:6]3[CH2:7][CH:8]([CH2:9][C:2]1([OH:1])[CH2:11]3)[CH2:10]2)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC1C2CC3CC(C2)CC1(O)C3
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: OC12CC3CC(CC(C3)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
To 1-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (0.47 g; 0.0028 mole), [prepared via a procedure of W. V. Curran and R. B. Angler, J. of Org. Chem., 94(11 ), 3668-70 (1969)] in dichloromethane (45 ml) is added triphenylmethyl chloride (0.78 g; 0.0028 mole) in dichloromethane (5 ml). This mixture is refluxed for 7 hours and then more triphenylmethyl chloride (0.35 g) is added and the reaction refluxed overnight. The reaction is stripped to dryness and the products separated via flash chromatography (eluted with 25% ethyl acetate/hexane) to obtain N-trityl-1-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine which is used directly in step B.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Si:14]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: OCCC1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Reaction time: 22 h
Yield: 85.9 %

Procedure:
2-(piperidin-4-yl)ethanol (2.00 g, 15.5 mmol), t-butylchlorodimethylsilane (2.57 g, 17.0 mmol), and imidazole (1.05 g, 15.5 mmol) were taken up in dichloromethane (15 mL) and stirred for 22 hours. This solution was added to aqueous K2CO3 (80 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a pale yellow oil. Silica gel chromatography (gradient elution dichloromethane+2.5% TEA/0-10% methanol) afforded a white solid. This solid was added to aqueous K2CO3 (60 mL) and extracted with dichloromethane+10% methanol (3×30 mL), the organics dried (MgSO4) and evaporated to give compound 292 as a yellow oil (3.24 g, 86%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: Cc1cccc(Oc2ccc(C[C@H](N)C(=O)O)cc2)n1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: Cc1cccc(Oc2ccc(C[C@H](Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)cc2)n1

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-methyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([CH:21]=1)[CH:19]=O>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:22])=[C:18]([CH2:19][C:10]2[S:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Cc1cccc(-c2cccs2)c1
Product: Cc1cccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)c1

Procedure:
2-(3-Methylphenyl)thiophene obtained in Reference Example 83-(1) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 377/379/381 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=1>C(O)C>[Cl:30][C:31]1[N:36]=[CH:35][N:34]=[C:33]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[N:32]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(Cl)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.84 g (6.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 4.54 mL (26.7 mmol) DIPEA were placed in 50 mL ethanol. 1.00 g (6.67 mmol) 2,4-dichloro-[1,3,5]triazine were added and the reaction mixture was stirred overnight at RT. The precipitated solid was suction filtered and dried,