Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][OH:23].C[O-].[Na+].[Na+].[Cl-]>O>[CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:23][CH3:22])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: CO
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1c(C(F)(F)F)cc([N+](=O)[O-])c(NN(C)C)c1[N+](=O)[O-]

Procedure:
To a stirred solution of 5.0 g. (0.015 mole) of N-(dimethylamino)-3-chloro-2,6-dinitro-4-trifluoromethylaniline and 50 ml. of anhydrous methanol was added 3.77 g. (0.015 mole) of a 21.8% methanolic sodium methoxide solution. The resultant mixture was stirred at room temperature for 6 hours and was then refluxed overnight for 16 hours. The methanol was then evaporated under vacuum leaving a yellow-solid residue. To the residue was added 150 ml. of water and the mixture stirred for 30 minutes to dissolve the NaCl and any other water-soluble materials. The mixture was then filtered and the water-insoluble solids were washed well with water. The solids were then dissolved in 30 ml. of refluxing 95% ethanol. On cooling, the product crystallized and was isolated by filtration to give 3.83 g. (77.7%) of a yellow crystalline solid; m.p. 109°-110.5° C. After recrystallization from 95% ethanol, the product melts at 110°-111.5° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1.[O:28]([CH2:35][CH:36]1[O:40][C:39](=[O:41])[N:38]([CH2:42][CH2:43]O)[CH2:37]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:43][CH2:42][N:38]3[CH2:37][CH:36]([CH2:35][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:40][C:39]3=[O:41])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1
Reactant: CC1(COc2ccc(O)cc2)OCCO1
Reactant: O=C1OC(COc2ccccc2)CN1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(COc2ccc(OCCN3CC(COc4ccccc4)OC3=O)cc2)OCCO1
Reaction time: 64 h
Yield: 62.9 %

Procedure:
Diethyl azodicarboxylate (1.6 ml) was added dropwise to an ice-bath cooled, stirred, solution of 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol (2.1 g), 5-phenoxymethyl-3-(2-hydroxyethyl)-oxazolidin-2-one (2.4 g) and triphenylphosphine (2.6 g) in anhydrous tetrahydrofuran (50 ml) under argon. The reaction mixture was left for 64 hours at 22° C. and then the solvent removed under reduced pressure. The residue was dissolved in dichloromethane and the solution seeded with 1,2-dicarbethoxyhydrazine. The solution was allowed to stand for 2 hours, the solid was collected and the filtrate was subjected to chromatography using 45% hexane in ethyl acetate grading to 40% hexane in ethyl acetate as eluent. The appropriate fractions were combined, evaporated, and the residue triturated with cyclohexane to give the 3-[2-(4-(2-methyl-1,3-dioxolan-2-ylmethoxy)phenoxy)ethyl]-5-(phenoxymethyl)oxazolidin-2-one (2.7 g) m.p. 75°-77° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)[CH3:2].Br[CH:22]([CH2:39]Br)[C:23]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:22]([C:23]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:24])[CH2:39]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(NCCNCc2ccccc2)cc1
Reactant: COCCN(C(=O)C(Br)CBr)c1ccc([N+](=O)[O-])cc1
Product: CCOc1ccc(N2CCN(Cc3ccccc3)C(C(=O)N(CCOC)c3ccc([N+](=O)[O-])cc3)C2)cc1

Procedure:
In a manner similar to Preparation 23, react N-(4-ethoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine with 2,3-dibromo-N-(2-methoxyethyl)-N-(4-nitrophenyl)propanamide to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH:5][CH3:6].CCN(CC)CC.ClC(Cl)(OC(=O)[O:26][C:27]([Cl:30])(Cl)Cl)Cl.CCOC(C)=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[C:27]([Cl:30])=[O:26])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1cc(Cl)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)c1cc(Cl)cc(C(F)(F)F)c1

Procedure:
3-Chloro-N-methyl-5-(trifluoromethyl)aniline (467, 1.24 g, 5.9 mmol) was dissolved in 15 mL dry toluene. To it was added Et3N (1.1 mL, 7.9 mmol), and the mixture was stirred in ice bath. To it was drop-wise added a pre-made solution of triphosgene (2.46 g, 8.3 mmol) in 7.5 mL dry toluene. The mixture was then stirred in ice bath for 3 hours. EtOAc (120 mL) and water (50 mL) were then poured into the mixture, and the organic phase was separated. It was washed with saturated NaHCO3 (aq) solution, dried, concentrated in vacuo to afford crude 3-chloro-5-(trifluoromethyl)phenyl(methyl)carbamic chloride (468) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:30])[C@@H:18]([NH:25][C:26](=[O:29])[O:27][CH3:28])[CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:11][C:7]=1[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[C:47]([C:52]2[NH:56][C:55]([C@@H:57]4[CH2:61][CH2:60][CH2:59][N:58]4[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=2)[CH:46]=[CH:45]3)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:28][O:27][C:26]([NH:25][C@@H:18]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:17]([N:13]1[CH2:14][CH2:15][CH2:16][C@H:12]1[C:10]1[NH:9][C:8]2[C:31]3[C:4]([CH2:5][CH2:6][C:7]=2[N:11]=1)=[CH:3][C:2]([C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[C:47]([C:52]1[NH:56][C:55]([C@@H:57]4[CH2:61][CH2:60][CH2:59][N:58]4[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[N:54][CH:53]=1)[CH:46]=[CH:45]2)=[CH:33][CH:32]=3)=[O:30])=[O:29]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(Br)cc1CC2)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1
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: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Temperature: 85 °C
Reaction time: 17 h
Yield: 39.8 %

Procedure:
Methyl (S)-2-((S)-2-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (211 mg, 0.408 mmol), (S)-tert-butyl 2-(5-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.449 mmol), Pd(PPh3)4 (47 mg, 0.0408 mmol) and K2CO3 (2M in H2O, 0.45 mL, 0.9 mmol) were suspended in DME (4 mL). The reaction mixture was degassed for 10 min with N2 then heated to 85° C. After 17 h, it was cooled to RT, diluted with MeOH, filtered over a thiol SPE column and concentrated. The crude residue was purified by silica column chromatography (0% to 40% MeOH/EtOAc) to afford the title compound (130 mg, 40%).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].CCN(CC)CC.[NH:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:29]([C:42](ON1C(=O)CCC1=O)=[O:43])[CH2:30][CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)(Cl)Cl>CN(C=O)C>[NH:28]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:29]([C:42]([NH:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:43])[CH2:30][CH2:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O

Procedure:
A suspension of H-Lys(Z)-OH (0.89 g, 3.18 mmol) in DMF (25 ml) was stirred with Et3N (0.5 ml) and Boc-Glu(OBzl)-OSu (1.58 g, 3.5 mmol) at 0° C for 1 hr and 25° C for 24 hr. The reaction mixture was worked up as described above in Example 2 to produce a clear oil which was crystallized from EtOAc and petroleum ether to yield 1.47 g (77.4%); mp 110°-112° C.; [α]D25 +6.0° (c 1, CHCl3). Anal. Calcd for C31H41N3O9 (599.69): C, 62.08; H, 6.89; N, 7.00. Found: C, 62.04; H, 6.96; N, 7.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ccncc3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ccncc3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyridin-4-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and benzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 3 h. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, 2H), 7.86 (dd, 2H), 7.62-7.46 (m, 7H), 7.17 (d, 2H), 7.07 (t, 1H), 6.71 (dd, 1H), 6.60 (d, 1H), 6.54 (s, 1H), 4.35 (s, 2H), 4.32 (s, 2H), 4.29 (s, 2H), 1.46 (s, 9H); MS 545 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:22])[NH:10][C@@H:11]([CH3:21])[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)O)C1C=CC=CC=1.CO.[OH-].[K+]>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:12]2[O:22][C:9](=[O:8])[NH:10][C@H:11]2[CH3:21])=[CH:19][CH:18]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@@H]1NC(=O)O[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
To [(S)-2-(4-Chloro-phenyl)-2-hydroxy-1-methyl-ethyl]-carbamic acid benzyl ester (2.7 mmol) in THF:MeOH was added 7.5N aqueous potassium hydroxide (10 mL), and the reaction was stirred at room temperature for 3 hours. Once no starting material was seen by analytical LCMS, the mixture was diluted with EtOAc and brine, and the organic layer was separated and purified by silica gel chromatography to give the desired product (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([C:26]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)=[CH:27][N:28]3[C:31]3[N:36]=[CH:35][N:34]=[C:33]([NH:37][CH3:38])[CH:32]=3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[C:29]4[C:25]([C:26]([C:39]5[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=5)=[CH:27][N:28]4[C:31]4[CH:32]=[C:33]([NH:37][CH3:38])[N:34]=[CH:35][N:36]=4)=[CH:24][CH:23]=3)[CH:17]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(N)c4)cc32)ncn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CNc1cc(-n2cc(-c3ccc(OC)cc3)c3ccc(-c4cccc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)c4)cc32)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (15.8 mg, 0.071 mmol) was added to a mixture solution of 6-(6-(3-aminophenyl)-3-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (20 mg, 0.047 mmol) in THF (1 mL) at room temperature. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by chromatography (silica gel, EA:Hx=1:1; DCM:MeOH=100:1; 20:1). The target compound was obtained as yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Na+].[I-]>CN(C=O)C.CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OCc3ccccc3)cc2n1Cc1ccccc1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) and acetone (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol), benzyl bromide (14.0 μl, 0.12 mmol), and catalytic amount of NaI to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33].O>C(O)(C)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:41]([C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:42])=[O:43])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
7.5 g (22.3 mmol) of (1S,2R)-(1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester and 2.7 g (26.8 mmol, 1.2 equiv) of triethylamine are dissolved in 100 g of isopropanol and heated to 60-65° C. 5.41 g (24.5 mmol, 1.1 eq) p-nitrophenyl-sulfonyl chloride are added in several portions within 30 minutes. The reaction mixture is kept at 60° C. for another 30 minutes. 10 g of water are added and the suspension is stirred for an additional 30 minutes at 60° C. The mixture is cooled to 25° C. within 90 min and the product is filtered off, washed with a mixture of isopropanol/water (1:1 v/v) and dried under vacuum to yield 11.23 g (96.5%) of white (1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[NH:35][CH2:34]2.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C:36](=[O:40])[NH:35][CH2:34]4)=[O:23])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc2c(c1)CNC2=O
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2cc(-c3cccc(C(=O)Nc4ccc5c(c4)CNC5=O)c3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (100 mg, 0.26 mmol), 5-aminoisoindolin-1-one (38 mg, 0.26 mmol), 1-methyl-1H-imidazole (84 mg, 1.02 mmol) and EDCI (196 mg, 1.02 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined and washed with brine (10 mL) then dried over Na2SO4. The residue was concentrated and triturated with MeOH (2 mL) to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(1-oxoisoindolin-5-yl)benzamide (26 mg, 20%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.68 (s, 1H), 9.97 (s, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.24-8.08 (m, 4 h), 7.82-7.64 (m, 4 h), 7.41 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=8.4 Hz), 4.39 (s, 2H), 4.02 (s, 3H), 3.76 (s, 3H). LC-MS: [M+H]+, 521.9, tR=1.434 min, HPLC: 96.12% at 214 nm, 96.79% at 254 nm, tR=3.673 min.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH2:21][CH2:20][NH:19][C:18]=3[CH:23]=2)=[O:13])=[CH:7][CH:6]=1)C.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[F:25][C:26]1[CH:27]=[C:28]([S:32]([N:19]2[C:18]3[CH:23]=[C:14]([C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:24])=[CH:6][CH:7]=4)=[O:13])[CH:15]=[CH:16][C:17]=3[O:22][CH2:21][CH2:20]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCCO3)cc1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(F)c2)CCO3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.1 %

Procedure:
Step 7 and 8. A solution of 4-[(3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl)-amino]-benzoic acid ethyl ester (27 mg, 0.085 mmol) in pyridine (0.4 mL) was treated with a solution of 3-fluoro-benzenesulfonyl chloride (25 mg, 0.13 mmol) in pyridine (0.2 mL). The resulting mixture was stirred at room temperature for 18 hours. The pyridine was evaporated, and the residual crude 4-{[4-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester was dissolved in ethanol (0.6 mL) and treated with KOH 3N (0.15 mL). The resulting mixture was stirred at room temperature overnight. The mixture was acidified with HCl 3N and evaporated. The residue was purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). 4-{[4-(3-Fluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid (17.1 mg, 44%) was obtained as an off-white solid, MS (ISP): m/e=455.0 (M−H).
Reaction SMILES: [F:1][C:2]([F:34])([O:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCOC(C1CC(C(OCC)=O)=C(C)NC=1C)=O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:34][C:2]([F:1])([O:6][C:7]1[CH:8]=[C:9]([C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:31])([F:32])[F:33])[CH:24]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: FC(F)C(F)(F)Oc1cccc(-c2ccc3c(-c4cccc(OC(F)(F)F)c4)cccc3n2)c1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: FC(F)C(F)(F)Oc1cccc([C@H]2CCc3c(cccc3-c3cccc(OC(F)(F)F)c3)N2)c1
Temperature: 58 °C

Procedure:
(also known as 4-oxo-2,6-di-phenanthren-9-yl-3,5-dioxa-4l5-phospha-cyclohepta[2,1-a; 3,4-a′]dinaphthalen-4-ol) (44.5 mg, 0.06 mmoL, 3 mol %), was added a solution made from 2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)quinoline (1.02 g, 2.12 mmoL) and toluene (3.61 g). The resulting slurry was stirred, heated to 58° C. and then stirred at 58° C. for 8 hours. The resulting mixture was then cooled to room temperature. (1S)-(+)-10-camphorsulfonic acid (148 mg, 0.30 eq) and additional diludine (160 mg, 0.3 eq.) were added and the resulting slurry was stirred at room temperature for 6 hours. To the resulting reaction mixture were added ethyl acetate (4 mL) and aqueous 2N Na2CO3 (6 mL). The phases of the resulting biphasic mixture wre separated. After the clear lower aqueous layer was mostly removed, the remaining organic phase and some precipitates were filtered and the filtrate was washed with 4N HCl for (3-5 times, 6 mL each time), followed by washing with 50% saturated aqueous Na2CO3 solution (2×). The resulting mixture was concentrated to yield the title compound, (R)-2-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-5-(3-(trifluoromethoxy)phenyl)-1,2,3,4-tetrahydroquinoline, as crude product, as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>O1CCCC1>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
A solution of 15 gm (63.3 mMol) 2-bromonaphthalene in 100 mL tetrahydrofuran was cooled to −78° C. and then 47.4 mL (75.9 mMol) n-butyllithium (1.6 M in hexane) were added. After stirring for about 1.5 hours, a solution of 19 mL (82.2 mMol) triisopropylborate in 30 mL tetrahydrofuran was added via addition funnel. The reaction mixture was allowed to warm to room temperature and was stirred for about 18 hours. The reaction mixture was then partitioned between ethyl acetate and 2 N hydrochloric acid. The phases were separated and the organic phase washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residual solid was suspended in hexanes and the mixture subjected to sonication. The suspension was then filtered to provide 8.3 gm (76%) of the title compound as a white solid.
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]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][NH:30][CH2:29]1>>[CH3:26][N:27]([CH3:32])[CH:28]1[CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(C)C1CNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CC(N(C)C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-dimethylazetidin-3-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.33 (d, J=1.95 Hz, 3H) 2.81 (s, 6H) 4.07-4.21 (m, 1H) 4.29 (br. s., 2H) 4.47-4.59 (m, 1H) 4.66 (m, J=7.80 Hz, 1H) 7.63 (br. s., 1H) 7.71-7.78 (m, 1H) 7.91-8.81 (m, 4H). ESI-MS m/z [M+H]+ 421.3.