Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.C[O-].[Na+]>C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:47][CH2:48][N:49]([CH2:52][CH2:53][S:54]([CH3:57])(=[O:56])=[O:55])[CH2:50][CH2:51]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: OCC(F)(F)F
Product: COc1cc(C2CCN(CCS(C)(=O)=O)CC2)c(C)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (200 mg, 0.41 mmol), 5-methyl-2-(methyloxy)-4-{1-[2-(methylsulfonyl)ethyl]-4-piperidinyl}aniline (120 mg, 0.37 mmol), and p-toluenesulfonic acid (186 mg, 0.98 mmol) were weighed into a 20 mL microwave vial. 7 mL of trifluoroethanol was added and the mixture was heated in the microwave to 150° C. for 2 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2.5 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (115 mg, 0.147 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.79 (s, 1H), 9.40 (d, J=6.97 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=5.13 Hz, 1H), 8.11 (d, J=2.57 Hz, 1H), 7.78 (dd, J=8.43, 2.20 Hz, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.56 (s, 1H), 7.42-7.49 (m, 1H), 7.34-7.42 (m, 1H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.97 (t, J=6.97 Hz, 1H), 6.89 (s, 1H), 6.59 (d, J=5.13 Hz, 1H), 3.99 (s, 3H), 3.81 (s, 3H), 3.28-3.32 (m, 2H), 3.06 (s, 3H), 3.02 (d, J=11.36 Hz, 2H), 2.74 (t, J=6.97 Hz, 2H), 2.60-2.70 (m, 1H), 2.20 (s, 3H), 2.04-2.15 (m, 2H), 1.65-1.76 (m, 4H). MS (ESI): 782 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:39][C:38]2=[CH:40][CH:41]=[C:35]([CH:36]=[CH:37]2)[NH:34][C:33](=[O:42])[CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.O.C([SiH](C(C)C)C(C)C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:39][C:38]2=[CH:37][CH:36]=[C:35]([CH:41]=[CH:40]2)[NH:34][C:33](=[O:42])[CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Yield: 33.9 %

Procedure:
20.0 mg (0.03 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)ureido]hexanoate were stirred in a mixture of 0.95 ml of TFA, 25 μl of water and 25 μl of triisopropylsilane at room temp. for 2 h. After the reaction was complete, the mixture was concentrated in vacuo and codistilled with toluene several times. The crude product obtained in this way was purified by preparative HPLC (acetonitrile/water+addition of 0.1% TFA). 5 mg of the title compound were obtained in this way as trifluoroacetate in the form of a colorless amorphous material.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C=O)C>[N:12]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1nccc2ncccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1nccc2ncccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF (40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture was stirred at 80° C. overnight. The mixture was poured into water (120 mL). The aqueous phase was extracted with EtOAc (150 mL×4). The combined organic layers were washed with brine (100 mL×3), dried over sodium sulfate, and concentrated under reduced pressure to give 3.4 g of the crude product as a brown solid. MS (ESI): m/z 172 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]3[CH:18]=[CH:19][S:20][C:11]=23)=[CH:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][C:2]2[S:3][C:4]([CH2:7][CH2:8][NH:9][C:10]3[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]4[CH:18]=[CH:19][S:20][C:11]=34)=[CH:5][N:6]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: N#Cc1cnc2ccsc2c1NCCc1cnc(N)s1
Solvent: ClCCl
Product: N#Cc1cnc2ccsc2c1NCCc1cnc(NC(=O)Nc2cccc(Cl)c2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.7 %

Procedure:
To a solution of 7-[2-(2-amino-thiazol-5-yl)-ethylamino]-thieno[3,2-b]pyridine-6-carbonitrile (27.1 mg, 0.09 mmol) in 2 ml of dichloromethane was added 3-chloro phenyl isocyanate (0.02 ml, 0.16 mmol). The resulting mixture was stirred at room temperature for 16 hr and filtered. Solids were washed with CH2Cl2, and the combined organics were concentrated. The residue was purified by chromatography on TLC plate with MeOH/CH2Cl2/NH3(aq)=1/20/0.1 to give 5.6 mg (14%) of a white solid. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.62-7.66 (m, 1H), 7.43 (d, J=5.2 Hz, 1H), 7.25-7.31 (m, 2H), 7.16 (s, 1H), 7.00-7.07 (m, 1H), 4.06 (t, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H). LC-MS (ESI) m/z 455.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:20]=[N:21][C:22]([Cl:26])=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:30](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:16]([C:19]3[CH:20]=[N:21][C:22]([Cl:26])=[C:23]([Br:25])[CH:24]=3)(=[O:18])=[O:17])[CH3:30])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cnc(Cl)c(Br)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cnc(Cl)c(Br)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a solution of [(R)-4-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared as described above in example 2-1, 1st step) (740 mg, 1.55 mmol) in acetonitrile (15 mL) was added methyl iodide (655 mg, 4.65 mmol) and potassium carbonate (641 mg, 4.65 mmol). The reaction mixture was stirred at 65° C. for 5 hours, then cooled to room temperature and filtered through a glass funnel. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (gradient elution, 0-10% methanol in dichloromethane) to afford {(R)-4-[(5-bromo-6-chloro-pyridine-3-sulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (680 mg, 89%) as a yellow solid. Ms cald. for C17H20BrClN4O4S 490, obsd. (ESI+) [(M+H)+] 491.
Reaction SMILES: N(C=CC=O)C1C=CC=CC=1.NC1C=CC=CC=1.[C:19]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])#[N:20].[C:33]([N:36]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)/[CH:37]=[CH:38]/[CH:39]=C(\C#N)/C(OCCCC)=O)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C>[C:33]([N:36]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)/[CH:37]=[CH:38]/[CH:39]=[C:21](\[C:19]#[N:20])/[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23])(=[O:35])[CH3:34]
Reactant: CCCCOC(=O)/C(C#N)=C/C=C/N(C(C)=O)c1ccccc1
Reactant: CCCCCCCCOC(=O)CC#N
Agent: O=CC=CNc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: Nc1ccccc1
Product: CCCCCCCCOC(=O)/C(C#N)=C/C=C/N(C(C)=O)c1ccccc1
Yield: 79 %

Procedure:
3-Anilinoacrolein-aniline (27.7 g, 0.125 mol) and n-octyl cyanoacetate (26.3 ml, 0.125 mol) are heated in 70 ml of acetic anhydride at 115° C. for 2 hours while bubbling with nitrogen. After cooling, 80 ml of methanol are added and precipitation is allowed to take place. The solid obtained is filtered off and rinsed with methanol. Drying is carried out. 36.4 g of a yellow powder (yield: 79%) of butyl (2E,4E)-5-[acetyl(phenyl)amino]-2-cyanopenta-2,4-dienoate are recovered, which powder is used as is in the following stage.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[S:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:18][C:12]1[S:11][C:10]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:9][C:8]=1[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2csc(C3OCCO3)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1sc(C2OCCO2)cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-(4-Phenoxy-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 109 (4.88 g, 19.7 mmol) and N-bromosuccinimide (3.85 g, 21.7 mmol) were dissolved in tetrahydrofuran (100 mL), and the solution was stirred for 4.5 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the residue was silica gel-filtered to obtain 2-(5-bromo-4-phenoxy-thiophen-2-yl)-[1,3]dioxolane (5.48 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.[CH3:19][NH:20][C:21](=[N:24][N+:25]([O-:27])=[O:26])SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:21]([NH:20][CH3:19])=[N:24][N+:25]([O-:27])=[O:26])=[N:7]1
Reactant: CNC(=N[N+](=O)[O-])SC
Reactant: NCCSCc1ccsn1
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 70 gives N-[2-(3-isothiazolymethylthio)ethyl]-N' -nitro-guanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea gives N-[2-(3-isothiazolylmethylthio)ethyl]-N' -methyl-N"-nitroguanidine.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:13]1([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][C:21]([CH3:1])([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:15]1
Reactant: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Reactant: CC(C)NC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCC(OCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C. under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D100, 9.47 g, 43.0 mmol) in THF (50 mL) was added and the resulting yellow solution was heated at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was added dropwise, the reaction was then allowed to warm to rt and left to stir for 3 days. 10% Citric acid (200 mL) was then added and the reaction mixture was concentrated by rotary evaporation. The residual mixture was diluted with H2O and extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D101, 10.0 g, 93%) as a brown oil.
Reaction SMILES: [N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][N:8]2[CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][CH2:11][CH2:10][CH:9]2[C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[NH:3][CH:2]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[CH3:27][C:26]1[C:21]([CH:9]2[CH2:10][CH2:11][CH2:12][CH:13]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:8]2[CH2:7][CH2:6][C:4]2[N:3]=[CH:2][N:1]([CH3:30])[CH:5]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cnc[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCc1cn(C)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 1′-[2-(3H-imidazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (167 mg, 0.46 mmol) in THF (5 mL) at 0° C. was added NaH (60%, 7 mg, 0.17 mmol). After 30 min at 0° C., MeI (10 mL, 0.15 mmol) was added and the reaction mixture was warmed to room temperature and stirred overnight. The next day the mixture was concentrated to afford a yellow foam. Purification by radial chromatography on silica gel (1 mm plate; using CH2Cl2/MeOH/NH4OH; 50:1:1→10:1:1) afforded the product as a yellow oil (23 mg, 41%). 1H NMR (CDCl3) δ 1.57-1.72 (m, 3H), 1.94-2.16 (m, 3H), 2.48-2.53 (m, 8H), 3.41 (s, 3H), 3.71 (s, 2H), 4.13 (d, 2H, J=9.0 Hz), 5.94 (br 2, 1H), 7.02-7.06 (m, 3H), 7.40 (d, 2H, J=9.0 Hz), 8.45 (br s, 2H). 13C NMR (CDCl3) δ 19.25, 23.34, 25.40, 32.42, 33.46, 50.08, 62.13, 115.93, 122.07, 132.50, 136.91, 138.83, 141.50, 147.32, 160.82. ES-MS m/z 376 [M+H]+. Anal. Calcd. for C1753H29N5.1.4H2O.0.4CH2Cl2: C, 64.65; H, 7.56; N, 16.11. Found: C, 65.01; H, 7.67; N, 15.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([NH:41][CH2:40][CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:14])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCN1CCCC1)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 79.7 %

Procedure:
Following General Procedure R, the title compound (388 mg, 80%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (411 mg, 0.77 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (294 mg, 1.53 mmol) and DMAP (cat.) in DMF (10 ml).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:35](=[O:37])[CH3:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CNCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(C)=O)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (0.6 g, 1.24 mmol) in CH2Cl2 (10 mL) and TEA (0.378 mL, 2.73 mmol) at 0° C. was added acetyl chloride (0.1 mL, 1.36 mmol). The reaction was allowed to warm to 25° C. over 19 h. The reaction was then taken up in CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and water (5 mL). The organics were washed with saturated aqueous sodium chloride (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified with Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate-hexanes, to provide 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester as a white solid (0.6 g, 92%). MS: 526 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH2:17]>C1COCC1>[C:1]([O:5][C:6](=[O:8])[NH:17][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution of di-tert-butyldicarbonate (29.314 g, 134.27 mmol) in THF (250 ml) was cooled to 0° C. and methyl amine (71 ml, 2M in THF) was added through a funnel. After stirring at 0° C. for 2 hours, the reaction mixture was allowed to warm up to room temperature and the solvent was removed using a rotary evaporator. The resulting residue was purified by flash chromatography to give methylcarbamic acid tert-butyl ester as a pale oil (11.518g, 65%). 1H NMR (CDCl3, 300 MHz) δ: 2.73(d, 3H, J=4.93 Hz), 1.45(s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH2:20])=[C:15]2[CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].O.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH:20][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N)c(SC)nn12
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(C)c1-c1cccc2c(Nc3ccccn3)c(SC)nn12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
After dissolving [7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (40 mg) in toluene (1 mL), 2-bromopyridine (0.013 mL), sodium t-butoxide (25 mg) and dichlorobis(tri-o-tolylphosphine)palladium complex (3 mg) were added and the mixture was heated and stirred at 120° C. for 5 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (12 mg) was obtained from the ethyl acetate:n-hexane (1:2) fraction as white crystals.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[C:15]4[C:20]=2[CH:19]=[C:18](B(O)O)[CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([C:11]2[CH:10]=[CH:9][C:8]3[C:13](=[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]4[C:20]([C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=2)=[CH:32][CH:33]=1
Reactant: Brc1ccc(Br)cc1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccc3c(-c4ccccc4)c4ccccc4c(-c4ccccc4)c3c2)cc1
Yield: 51.5 %

Procedure:
An amount of 3.74 g (10 mmol) of 9,10-diphenylanthracene-2-boronic acid synthesized in the same manner as in Exemplary Synthesis 1, 9.44 g (40 mmol) of p-dibromobenzene, and 300 mg of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 60 ml of toluene and 15 ml of ethanol. Then, 30 ml of 2M sodium carbonate solution was added and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 2.32 g (5.15 mmol) of 2-(4-bromophenyl)-9,10-diphenylanthracene. The yield was 51.5%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N1CCC[C@H]1C#N.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:36]3[CH2:35][CH2:34][CH2:33][C@H:31]3[C:32]#[N:37])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#C[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)[C@H](C(=O)N1CCC[C@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol), (S)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a yellow film (4 mg, 29%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.04-1.13 (m, 1H), 2.12-2.17 (m, 2H), 2.25-2.29 (m, 2H), 2.60-2.63 (m, 1H), 3.72-3.75 (m, 1H), 3.83-3.87 (m, 1H), 4.90 (d, J=13.7 Hz, 1H), 5.05 (d, J=12.7 Hz, 1H), 5.50 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd for C19H20ClN5O2, 386; found, 386.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Mg]Br>CCOCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[CH3:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
At 0° C. to a solution of 3-(3,4-dichlorophenyl)-N-methoxy-N-methylpropanamide (569 mg, 2.17 mmol) in ether (10 mL) was added drop wise methyl magnesium bromide (2.17 mL, 6.51 mmol) and the solution was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm up to rt and stirred for 18 h. The reaction mixture was cooled to 0° C. and brine was added to quench the reaction. The aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50% over 20 min, column 40 g, flow rate 40 mL/min) to give Intermediate 15B (292 mg, 1.34 mmol, 62.0% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (3H, s), 2.75 (2H, t, J=6.9 Hz), 2.80-2.90 (2H, m), 7.02 (1H, dd, J=8.2, 2.2 Hz), 7.28 (1H, d, J=2.2 Hz), 7.33 (1H, d, J=8.2 Hz).