Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>COCCOC.CCO.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>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[N:6][CH:5]=[C:4]([C:8]4[C:9]5[CH:23]=[CH:22][NH:21][C:10]=5[N:11]=[C:12]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=5)[N:13]=4)[CH:3]=3)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: COCCOC
Solvent: O
Solvent: CCO
Product: Cc1cccc(-c2nc(-c3cncc(-c4ccc(C(=O)N5CCN(C)CC5)cc4)c3)c3cc[nH]c3n2)n1

Procedure:
To a solution of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.273 mmol, 100 mg) and 4-(4-methylpiperazine-1-carbonyl)phenyl-boronic acid pinacol ester (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.1 eq, 0.300 mmol, 101 mg) in DME/EtOH (1:1, 2 ml), aqueous Na2CO3 solution (2 M, 3 eq, 0.82 mmol, 0.41 ml) and Pd(PPh3)4 (0.05 eq, 0.014 mmol, 16 mg) are added. The resulting mixture is heated using microwave radiation at 140° C. for 20 min. The mixture is diluted with water, basified with aqueous NaOH (1 M), extracted with DCM, and the organic layer is dried with MgSO4 and filtered. After evaporation of the solvent the crude product is purified by reversed phase HPLC giving the title compound; [M+H]+=490; 1H-NMR (400 MHz, CDCl3): δ 13.09 (s, 1H), 9.50 (d, 1H), 8.98 (d, 1H), 8.78 (d, 1H), 8.66 (d, 1H), 7.84 (t, 1H), 7.76 (d, 2H), 7.58 (d, 2H), 7.45 (m, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 3.84 (m, 2H), 3.53 (m, 2H), 2.74 (s, 3H), 2.55-2.35 (m, 4H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:14][CH2:15][CH3:16])[C:10]=1[O:11][CH2:12][CH3:13])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:39]/[C:40](=[N:57]\[H])/[C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:49]=1[NH:48][CH:47]=[C:46]2[CH2:50][CH2:51][C:52]([O:54][CH2:55]C)=[O:53].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:57]=[C:40]([C:41]3[CH:42]=[CH:43][CH:44]=[C:45]4[C:49]=3[NH:48][CH:47]=[C:46]4[CH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])[N:39]=2)[CH:8]=[C:9]([O:14][CH2:15][CH3:16])[C:10]=1[O:11][CH2:12][CH3:13]
Reactant: CCOc1cc(C(=O)O)cc(Cl)c1OCC
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOc1cc(-c2nc(-c3cccc4c(CCC(=O)OC)c[nH]c34)no2)cc(Cl)c1OCC
Reaction time: 2 h
Yield: 11.2 %

Procedure:
To a solution of 3-chloro-4,5-bis(ethyloxy)benzoic acid (D69) (184 mg) in tetrahydrofuran (10 mL) stirred at room temperature was added EDCI (192 mg) and HOBT (153 mg). The reaction mixture was stirred for 2 h, followed by addition of methyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (131 mg). The reaction mixture was stirred at 60° C. for another 2 h, and then TBAF (523 mg) was added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 130° C. for 3 h. After cooling the reaction, the solvent was removed. Water (10 mL) and ethyl acetate (30 mL) was added, the organic layer was separated and the solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford methyl 3-(7-{5-[3-chloro-4,5-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D70) (25 mg) as a white solid. δH (CDCl3, 400 MHz): 1.46 (3H, t), 1.55 (3H, m), 2.78 (2H, t), 3.18 (2H, t), 3.70 (3H, s), 4.22-4.28 (4H, m), 7.21 (1H, d), 7.29 (1H, t), 7.67 (1H, d), 7.81 (1H, t), 7.93 (1H, d), 8.13 (1H, d), 9.60 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>ClCCCl>[Cl:1][CH2:2][CH2:3][C:4]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: c1ccoc1
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCCl)c1ccco1
Temperature: 0 °C
Yield: 11 %

Procedure:
At 25°, 3-chloropropionyl chloride (25.4 g, 0.20 mole) was added to a suspension of anhydrous aluminum chloride (27.1 g, 0.20 mole) in 1,2-dichloroethane (DCE). The mixture was stirred until the aluminum chloride had nearly dissolved. This solution was added at 0°-5° during 15 minutes to a solution of furan (13.6 g, 0.2 mole) in 100 ml of DCE. The reaction mixture became very dark and a tan precipitate was deposited. The reaction mixture was then immediately poured into 1 of ice-water. An emulsion of some brown precipitate formed. This mixture was extracted with diethyl ether (five times, 150 ml), and the combined ether extract was filtered through a column of 150 g of silica gel. The column was then washed with 200 ml of ether and the combined eluants were concentrated at reduced pressure (40°) to 100 ml. The solution was then washed with 100 ml of saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, treated with activated carbon, and evaporated at reduced pressure to give a liquid (3.5 g) which rapidly darkened at room temperature. It was stored at -10°. PMR spectroscopy indicated the product was about 75% desired copound. The mixture was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[OH:22])=[N:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[C:36](O)=[O:37])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(N=C=NC(C)C)(C)C.O[Li].O.C(O)(=O)C>ClCCl.O.C(OCC)(=O)C>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[C:36](=[O:37])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[OH:22])=[N:12][NH:13][CH:14]=2)=[CH:4][CH:3]=1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Agent: CC(C)N=C=NC(C)C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of compound 24A (520 mg, 1.7 mmol) and N-Boc-2(S)-piperidinecarboxylic acid (8A) (584 mg, 2.55 mmol) in anhydrous dichloromethane (30 mL) was added N,N′-diisopropylcarbodiimide (DIPC, 0.4 mL, 2.55 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed. To the residua were added THF (40 mL) and methanol (40 mL) and a solution of LiOH.H2O (2.0 g, 47.68 mmol) in water (20 mL). The mixture was stirred at rt for 3 h. It was then neutralized with acetic acid (3 mL, 52.41 mmol). The mixture was diluted with ethyl acetate (˜100 mL), washed with brine, and dried over sodium sulfate. It was filtered, concentrated and filtered again to remove diisopropylurea. The filtrate was purified with silica column chromatography eluting with hexanes/ethyl acetate (v/v 2/1, 3/2, 1/1) to provide the title compound (25A, 500 mg) as a yellowish solid in 57.2% yield. 1H NMR (CDCl3, 500 MHz) δ 10.62 (br s, 1H), 8.71 (d, 1H, J=2.0 Hz), 8.35 (br s, 1H), 7.84 (s, 1H), 7.55 (s, 4H), 7.22 (dd, 1H, J=9.0, 2.0 Hz), 6.99 (d, 1H, J=9.0 Hz), 4.90 (s, 1H), 4.05 (m, 1H), 2.90 (t, 1H, J=11.5 Hz), 2.35 (m, 1H), 1.80-1.30 (m, 16H). LCMS (ESI) m/z 587.15 (MNa+), 521.05 (MH+), 421.06; HPLC: tR=5.32 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (102 mg).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH3:30][N:31]([S:53]([CH3:56])(=[O:55])=[O:54])[C:32]1[CH:33]=[C:34]([C:50](O)=[O:51])[C:35]2[CH2:36][CH2:37][N:38]([CH:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])[C:39](=[O:42])[C:40]=2[CH:41]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:50]([C:34]1[C:35]2[CH2:36][CH2:37][N:38]([CH:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])[C:39](=[O:42])[C:40]=2[CH:41]=[C:32]([N:31]([CH3:30])[S:53]([CH3:56])(=[O:55])=[O:54])[CH:33]=1)=[O:51])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(N(C)S(C)(=O)=O)cc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(N(C)S(C)(=O)=O)cc2C1=O
Reaction time: 20 h
Yield: 79.4 %

Procedure:
Poured into a suspension of 233 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 278 mg of 7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 12 mg of hydroxybenzotriazole and 142 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 cm3 of dichloromethane is 0.4 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 20 h at a temperature close to 20° C. 20 cm3 of water are added to the reaction medium. After decanting, the organic phase is filtered through a pellet of 15 g of 40-63 μm silica. The silica pellet is washed firstly with 150 cm3 of dichloromethane then secondly with 150 cm3 of a mixture of 50% ethyl acetate/50% dichloromethane. This second filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 330 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white foam.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=2)[CH:8]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Solvent: CC#N
Product: Nc1ccc2ccn(Cc3ccccc3)c2c1

Procedure:
1-Benzyl-1H-indol-6-ylamine (B-2) was synthesized following the general scheme above starting from 6-nitroindole and benzyl bromide. Overall yield (˜40%). HPLC ret. time 2.19 min, 10-99% CH3CN, 5 min run; ESI-MS 223.3 m/z (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:15][C:16]#[N:17].[NH4+].BrBr>C(O)(=O)C>[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[C:11]([S:15][C:16]#[N:17])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(Br)cc1N
Agent: BrBr
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(SC#N)c(Br)cc1N
Temperature: 25 °C

Procedure:
In a 100 ml three-neck round bottom flask equipped with an internal thermometer and magnetic stirrer, a solution of 3.26 g (0.0116 mol) of ethyl 2-amino-4-bromobenzoate hydrochloride, 2.12 g (0.0279 mol) of ammonium thiocyanate and 30 ml of acetic acid was cooled to 15° C. Bromine (1.86 g, 0.0116 mol) was then added dropwise with stirring. A precipitate formed. When the addition was complete, the solution was allowed to warm to room temperature, and to stir for an hour. The product was filtered, dried under nitrogen, and recrystallized from hexane and ethyl acetate to furnish crystalline ethyl 2-amino-4-bromo-5-thiocyanatobenzoate: yield 2.05 g (59%); m.p. 149°-150° C.; ir(KBr) 3487 cm, 3453, 3375, 3346, 2980, 2146, 1697, 1614 among others; 1H--NMR(CDCl3) 1.4 ppm (triplet, 3H, CH2CH3), 4.3 (quartet, 2H, CH2CH3), 6.0 (broad singlet), 6.9 (singlet, 1H, aromatic H), 8.1 (singlet, 1H aromatic H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:20](O)(=[O:22])[CH3:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[C:20]([C:8]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: C=CCOc1cc(CC(=O)OC)cc(OCC=C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCOc1cc(CC(=O)OC)c(C(C)=O)c(OCC=C)c1
Temperature: 4 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
Methyl 3,5-diallyloxyphenylacetate (40 g, 0.14 mol) obtained in Example 5, Step 1 was dissolved in trifluoroacetic acid (0.15 L). After the solution was cooled to 4° C., acetic acid (9.5 mL, 0.17 mol) and trifluoroacetic anhydride (40 mL, 0.28 mol) were added thereto, followed by stirring at 4° C. for 3.5 hours. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20-1/6) to obtain methyl 2-acetyl-3,5-diallyloxyphenylacetate (30 g, 65%).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10](I)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:13]1[CH:17]=[CH:16][C:15]([N:18]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[C:37]([OH:38])=[CH:36][C:35]([C:39]4[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([F:46])[CH:40]=4)=[C:34]([F:47])[CH:33]=2)[C:27](=[O:48])[CH:26]=[CH:25]3)(=[O:21])=[O:20])=[N:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[F:45][C:43]1[CH:44]=[C:39]([C:35]2[C:34]([F:47])=[CH:33][C:32]([N:28]3[C:29]4[C:24](=[CH:23][C:22]([S:19](=[O:21])(=[O:20])[N:18]([C:15]5[CH:16]=[CH:17][O:13][N:14]=5)[CH2:49][C:50]5[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=5)=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]3=[O:48])=[C:37]([O:38][CH:10]3[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]3)[CH:36]=2)[CH:40]=[C:41]([F:46])[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3OC3CN(C(=O)OC(C)(C)C)C3)c2)cc1

Procedure:
N-boc-3-iodoazetidine (0.076 ml, 0.268 mmol) was added to a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (0.085 g, 0.134 mmol) and cesium carbonate (0.087 g, 0.268 mmol) in acetonitrile (0.335 ml) and stirred over night. LCMS indicated that the reaction was complete (mass—Boc group). The resulting mixture was transferred to a sep. funnel containing water and the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The yield was assumed to be quantitative and taken directly on to the next step. m/z (ESI) 691.0 (M+1-Boc)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16]([OH:18])=O)=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O[NH:64][C:65]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[NH:66].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(#N)C.CN(C=O)C>[C:67]1([C:65]2[N:66]=[C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:12]([C:9]3[CH:10]=[CH:11][C:5]4[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:13])[O:18][N:64]=2)[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: N=C(NO)c1ccccc1
Reactant: O=C1COc2ccc(C(=O)c3ccccc3C(=O)O)cc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F[P-](F)(F)(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1COc2ccc(C(=O)c3ccccc3-c3nc(-c4ccccc4)no3)cc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.6 %

Procedure:
2-[(3-Oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]benzoic acid (100 mg, 0.34 mmol.) was taken into DMF (1 mL) followed by addition of 4-methylmorpholine (75 uL, 0.7 mmol.) and PyBOP (177 mg, 0.34 mmol.) and the resulting solution was stirred for 15 minutes at room temperature. N-Hydroxybenzenecarboximidamide (46 mg, 0.34 mmol.) was added to the solution thus obtained and the mixture was allowed to stir an additional hour then partitioned with ethyl acetate and water. The organic layer was washed with water (3×), 10% aqueous citric acid (2×), saturated aqueous sodium bicarbonate (1×) and brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded a crystalline solid that was suspended in anhydrous 1:1 THF: acetonitrile (1 mL) followed by addition of 1M TBAF in THF (300 uL) and the mixture was allowed to stir at room temperature under a nitrogen atmosphere for 24 hours. The solvent was removed in vacuo and the residue partitioned with ethyl acetate and water. The organic layer was washed twice with additional water and a crystalline solid was obtained from the organic layer. The solid product was collected by filtration and suspended in methanol. The solid was again collected by filtration, washed with additional methanol and dried in vacuo to give 6-{[2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-2H-1,4-benzoxazin-3(4H)-one (63 mg, 47% yield) as a white crystalline solid. 1H NMR (400 MHz, d4-MeOH): 8.26 (d, 1H), 7.91 (d, 2H), 7.83-7.80 (m, 2H), 7.62 (d, 1H), 7.52-7.44 (m, 4H), 7.35 (dd, 1H), 6.96 (d, 1H), 4.61 (s, 2H). MS (EI) for C23H15N3O4: 398 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1)=[O:11]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoic acid. ESI-MS (m/z): 327 [M+1]+.
Reaction SMILES: [CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)=[O:2].[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>N1C=CC=CC=1>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:17][S:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:3]([CH:1]=[O:2])[CH2:4][CH2:5][CH2:6]2)(=[O:15])=[O:14]
Reactant: Nc1nccs1
Reactant: O=CN1CCCc2cc(S(=O)(=O)Cl)ccc21
Solvent: c1ccncc1
Product: O=CN1CCCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 0 %

Procedure:
1-Formyl-1,2,3,4-tetrahydro-quinoline-6-sulfonyl chloride (10.0 g, 0.04 mol) was added to a stirring solution of 2-aminothiazole (3.9 g, 0.04 mol) in pyridine (15 mL), under N2 at 0° C. This mixture was allowed to warm to room temperature and was stirred for 19 hours. The mixture was purified via silica gel chromatography using 10% MeOH in CH2Cl2 to obtain the sulfonamide (1.50 g, 0.005 mmol, 12% yield). LC/MS (10-99%) M/Z: M+1 obs=324.3; tR=2.21 min.
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:6][CH:5]([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)[CH:10]=2)[CH2:4]1.C=O.O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl>ClCCl.C(O)(=O)C.O.CCOC(C)=O.CCOCC>[ClH:1].[ClH:1].[CH2:26]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:11]2[CH:10]=[C:9]([O:8][CH2:7][CH:5]3[CH2:4][N:3]([CH3:36])[CH2:6]3)[N:14]=[N:13][C:12]=2[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCc1nnc(OCC2CNC2)cc1-c1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCc1nnc(OCC2CN(C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 144.1 %

Procedure:
To a solution of the above pyridazine dihydrochloride (0.3 mmol, 143 mg) in dichloromethane (2 mL) was added formaldehyde solution in water (37%, 10 mmol, 1.0 mL), and 2 drops of acetic acid. Then sodium triacetoxyborohydride (10 mmol, 2.12 g) was added. The mixture was stirred at room temperature for 0.5 hour then condensed, diluted with water/EtOAc, and neutralized with NaHCO3 powder. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N ammonia in MeOH) to give a solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (106 mg). LCMS: m/z 419 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.84 (1H, s), 7.45-7.55 (4H, m), 7.36-7.40 (2H, m), 7.31-7.35 (1H, m), 7.20-7.24 (2H, m), 5.21 (2H, s), 4.42 (2H, d), 3.63-3.68 (2H, m), 3.02-3.17 (4H, m), 2.87 (3H, s), 2.25-2.33 (1H, m), 1.62-1.74 (2H, m), 1.23-1.33 (2H, m), 0.82 (3H, t).