Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:14]Br.C(Cl)(Cl)Cl.[OH-].[Na+]>CO>[Br:14][C:9]1[CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([NH2:6])=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:8]=1
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(Br)cc(C(C)C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-diisopropylaniline (2.0 mL, 11 mmol) in methanol (80 mL) was treated dropwise with bromine (543 μL, 10.6 mmol). The solution was stirred at room temperature for 15 min. Chloroform and 0.1 N NaOH were added and the organic layer was dried (Na2SO4), filtered and concentrated to an orange liquid. Kugelrohr distillation (110° C. @ 0.06 Torr) afforded a colorless liquid (2.22 g 79%): 1H NMR (400 MHz) δ1.25 (d, J=6.4 Hz, 12H), 2.88 (m, 2H), 3.70 (brs, 2H), 7.11 (s, 2H); 13C NMR δ22.1, 27.9, 111.0, 125.6, 134.5, 139.3; Anal calcd for C12H19BrN: C, 56.26; H, 7.08; Br, 31.19; Found, C, 56.24; H, 7.07; Br, 30.98.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C:42]1([CH2:46][OH:47])[CH2:45][CH2:44][CH2:43]1>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:41][C:42]4([CH2:46][OH:47])[CH2:45][CH2:44][CH2:43]4)=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: NC1(CO)CCC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3(CO)CCC3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (1-aminocyclobutyl)methanol (27 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (54 mg, 53%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[Cl:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 61 mg (0.36 mmol, 1.5 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (52% of theory)
Reaction SMILES: [OH:1][CH:2]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][N:31]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:46])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[OH:1][CH:2]([C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][N+:31]=1[O-:46])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cccnc1C(O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc[n+]([O-])c1C(O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 46.5 %

Procedure:
To a solution of N-[4-[hydroxy-(3-methoxypyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (350 mg) in tetrahydrofuran (30 ml) was added 3-chloroperbenzoic acid (70%, 0.26 g) at 0° C., and the mixture was stirred at room temperature for 64 hours. To the mixture was added sodium thiosulfate, and the mixture was stirred for a few minutes and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate→ethanol/ethyl acetate=1:4) recrystallized from tetra-hydrofuran-hexane to give N-[4-[hydroxy(3-methoxy-1-oxidopyridin-2-yl)methyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 170) (168 mg) as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])=[CH:11][C:10]=1[CH3:35])(C)(C)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:35][C:10]1[CH:11]=[C:12]([S:15][CH:16]([C:18]2[C:19]([CH3:34])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH3:17])[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:36])=[O:5]
Reactant: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(SC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 2 h

Procedure:
0.322 g (0.62 mmol) of the above prepared (2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid tert-butyl ester, containing some methyl ester, was dissolved in 3.8 ml of THF/EtOH=1/1, treated with 1.87 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/HCl dil., extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after crystallization from AcOEt/hexane, 0.276 g of the title compound as off-white solid of mp. 115–117° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCN
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), ethyl 3-aminopropanoate hydrochloride (6.71 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=477.5.
Reaction SMILES: C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[CH2:23]([NH:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[CH:36]=2)[NH:31]1)=[O:29])[CH2:24][CH2:25][CH3:26].[CH2:41]([O:48][C:49]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[CH2:23]([NH:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:39][CH3:40])[CH:36]=2)[N:31]1[C:54](=[O:55])[C@H:52]([CH3:53])[NH:51][C:49]([O:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:50])=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCNC(=O)C1Cc2cc(OC)ccc2N1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNC(=O)C1Cc2cc(OC)ccc2N1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Triethylamine (1.12 ml, 8 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (0.815 g, 3.2 mmol) were added to a cooled (0° C.) solution of 5-methoxyindoline-2(R/S)-carboxylic acid butylamide (0.500 g, 2.01 mmol) and N-benzyloxycarbonyl-L-alanine (0.4956 g, 2.22 mmol) dissolved in dichloromethane (25 ml), under nitrogen. The mixture was stirred at room temperature for 22 hours. It was then washed with 10% citric acid (3×30 ml), 5% NaHCO3 (3×30 ml) and water (30 ml). The organic phase was dried and concentrated and the residue was purified by chromatography on a column of silica gel, using a 1/1 petroleum ether/ethyl acetate mixture as eluent. A white solid was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][N:14]2[CH2:13][CH2:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[CH2:7][C:8]4[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=4[C@H:10]3[CH2:15]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2c(c1)Cc1ccccc1[C@H]1CNCCN21
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(F)cc3Cc3ccccc3[C@H]2C1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bS)-8-fluoro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 91%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:20]=2)=[CH:27][CH:28]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{1-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonamide (0.15 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a light brown solid (0.01 g, 2%). MS (ISP) 432.3 [(M+H)+]; mp 281° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33](I)[CH3:34]>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:33][CH3:34])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: CC#N
Product: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Yield: 66.6 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (102 mg, 0.2 mmol) in acetonitrile (10 mL) was treated with ethyl iodide (34 mg, 17.4 μL, 0.2 mmol). The reaction mixture was heated for 24 h at 50° C., until analysis (TLC/LCMS) showed complete consumption of starting material. The reaction mixture was allowed to cool to ambient temperature and was then concentrated in vacuo. The resultant residue was partitioned between ethyl acetate (10 mL) and 1M sodium carbonate solution (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by chromatography (silica, Si-SPE, EtOAc) to afford the title compound as a white solid (72 mg, 60%). 1H NMR (CDCl3, 400 MHz): 9.56 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.25-8.22 (m, 2H), 7.67-7.62 (m, 1H), 7.54-7.49 (m, 2H), 5.15 (s, 1H), 2.96 (s, 2H), 2.48 (s, 2H), 2.23 (s, 4H), 2.02 (d, J=16.9 Hz, 2H), 1.18-1.04 (m, 3H). LCMS (Method G): RT=3.5 min, M+H+=541.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[CH:12]1([C:18]([C:20]2[C:21]([N:26]([CH2:30][CH3:31])[C:27](=[O:29])[CH3:28])=[N:22][CH:23]=[CH:24][CH:25]=2)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O>[CH:12]1([C:18]2[C:20]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:26]([CH2:30][CH3:31])[C:27](=[O:29])[CH:28]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCN(C(C)=O)c1ncccc1C(=O)C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)cc(C2CCCCC2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Under ice-cooling, 2.9 g of 90% potassium tert-butoxide was added to 70 ml of tetrahydrofuran solution containing 6.4 g of N-(3-cyclohexylcarbonyl-2-pyridyl)-N-ethylacetamide, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) to give 4.5 g of 4-cyclohexyl-1-ethyl-1,8-naphthyridin-2(1H)-one.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]O.C(N(C(C)C)CC)(C)C.[CH2:34]([C:38]1[N:39](C(OC(C)(C)C)=O)[CH:40]=[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:42]=1)[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH2:34]([C:38]1[N:42]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[C:41]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:40][N:39]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1nc(CCC(=O)OCC)cn1C(=O)OC(C)(C)C
Reactant: OCc1ccccc1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ncc(CCC(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of trifluoromethanesulfonic anhydride (163 μL, 0.966 mmol) in methylene chloride (1 mL) held at -75° C. under argon was added 2-chlorobenzyl alcohol (138 mg, 0.966 mmol) and diisopropylethylamine (168 μL, 0.966 mmol) in methylene chloride (2 mL) over one minute. After being stirred for 15 minutes, a solution of ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate (285 mg, 0.878 mmol) in methylene chloride (2 mL) was added over a 3-minute interval at -75° C. The reaction mixture was then allowed to warm to room temperature and was stirred for 18 hours. The solvent was evaporated, and this crude product was flash chromatographed over silica gel with a gradient of ethyl acetate in hexane to give 179 mg (58%) of ethyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-propanoate as an oil. TLC on silica gel with 1:1 hexane/ethyl acetate showed a single product with an Rf of 0.41.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)#[CH:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:2]2[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C)c(N)c(Br)n1
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(N)c(C#Cc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of Cul (5.7 mg, 30 μmol) in triethylamine (1.6 ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (120 mg, 0.60 mmol, described in Example 12), (PPh3)2PdCl2 (21 mg, 30 μmol), and 1-ethynyl-3-chlorobenzene (98 mg, 0.72 mmol). The reaction mixture was stirred for 30 min. at room temperature and for 3 h under reflux. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 4:1) to yield 39 mg (0.15 mmol, 25%) of (2-(3-chloro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Yield: 82 %

Procedure:
A suspension of methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) (1.35 g, 5.29 mmol), pyridinium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4 dihydro-2H-pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20 mL) was refluxed 5 h under argon. The suspension was turned into the clear solution. The solution was cooled and the excess solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with dilute NaHCO3 solution (satd. NaHCO3 soln/H2O: 1:9). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (100% hexanes→5:95 EtOAc:hexanes) to get methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) as a white solid (1.47 g, 4.34 mmol, 82% yield). 1H NMR (DMSO-d6) δ ppm 8.22 (d, J=1.4 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.68 (dd, J=7.2, 1.6 Hz, 1H),), 6.02 (dd, J=8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79 (m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.73 (m, 1H). 1.60-1.58 (m, 2H); ESIMS found for C14H15BrN2O3 m/z 340.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].Cl>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 465 parts of 1,3-difluorobenzene and 133.3 parts of aluminum trichloride was added dropwise a mixture of 110.1 parts of 4-chloro-3-nitro-benzoyl chloride and 116 parts of aluminum trichloride at 70° C. After stirring for 2 hours at reflux temperature, the reaction mixture was poured into ice-water. There were added 127 parts of hydrochloric acid and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 130 parts (87.4%) of (4-chloro-3-nitrophenyl) (2,4-difluorophenyl)methanone; mp. 90.5° C.(interm. 1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[CH:14]1(O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:14]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OC1CCCCC1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1nn(C2CCCCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a mixture of methyl 1H-indazole-3-carboxylate (5.00 g), cyclohexanol (9.00 mL), triphenylphosphine (14.9 g) and tetrahydrofuran (100 mL) was added 40% diethyl azodicarboxylate toluene solution (25.6 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the mixture was stirred at 0° C. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, volume ratio) to give the title object compound (6.84 g, 93%) as a pale-red oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:12])[OH:11])=[O:8])C(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][CH2:2][C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:11])[OH:12])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of tert-butylglycylbiotin (0.271 g, 0.758 mmol) in CH2Cl2 (0.5 mL) was added 0.5 mL trifluoroacetic acid. The reaction mixture was stirred at room temperature for 2 h, concentrated, and triturated with anhydrous diethyl ether. The off-white precipitate was collected to yield 0.209 g (0.694 mmol, 92%) of glycylbiotin, Mass spec [M+H]+ at m/z 302.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29]>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3cncnc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (466 mg), a solution of ammonia in methanol (about 7 mol/L, 18.6 mL) and tetrahydrofuran (6.2 mL) was stirred at room temperature for 48 hours. The precipitate was collected by filtration, washed with methanol, and then dried under reduced pressure to obtain the title compound (370 mg). 1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 4.44 (2H, s), 6.70 (1H, dd, J=2.3, 8.5 Hz), 6.89 (1H, d, J=2.3 Hz), 7.34-7.41 (1H, m), 7.51 (1H, d, J=8.5 Hz), 7.63-7.77 (2H, m), 7.79-7.86 (2H, m), 9.13 (1H, s), 9.14 (2H, s), 11.45 (1H, s).