Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH3:19])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:51])[C:23]([C:26]1[CH:31]=[CH:30][C:29](C#CC2C=C(C3CC3)C3OC4(CC4)CC(C)(C)C=3C=2)=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:20][O:21][C:22](=[O:51])[C:23]([C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[CH:7][C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:19])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1)([CH3:25])[CH3:24]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene (Intermediate 168, 0.16 g, 0.63 mmol), methyl-2-(4-iodophenyl)-2-methyl-propionate (Reagent 2, 0.18 g, 0.58 mmol), triethyl amine (3 mL), copper(I)iodide (0.048 g, 0.25 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol) followed by flash column chromatography over silica gel (230–400 mesh) and preparative normal phase HPLC using 6% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.14 g, 56%).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:12][CH2:13][CH2:14][OH:15]>CN(C=O)C>[F:10][C:8]1[CH:7]=[CH:6][C:5]2[S:11][CH2:12][CH2:13][CH2:14][O:15][C:4]=2[CH:9]=1
Reactant: OCCCSc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)OCCCS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (177 mg, 4.42 mmol) was added to a solution of 3-[(2,4-difluorophenyl)thio]propan-1-ol (0.41 g, 2.01 mmol) in DMF (40 mL) and the mixture stirred at RT for 24 hours. The solvent was removed in vacuo and iced water (200 mL) added. The mixture was extracted into ethyl acetate and the organics washed with brine (40 mL), dried (MgSO4), filtered and reduced in vacuo to give a white solid which was chromatographed on silica, eluting with 0-10% ethyl acetate in isohexane, to give the desired compound as a colourless oil (110 mg).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C1(C)C=CC(S([NH:28][NH2:29])(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH:28]1[C:2]2[C:10]3[C:5]([CH2:4][C:3]=2[C:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:29]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C1C(=Cc2ccc(O)cc2)Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
A mixture of 4-(1-oxoindan-2-ylidenemethyl)phenol (1.67 g, Chem. Ber. 1901, 34, 413), p-toluenesulphonyl hydrazine (1.95 g), p-toluenesulphonic acid (0.27 g) and ethanol (15 ml) was boiled under reflux for 72 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80° C./ethyl acetate (1:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a residue which was triturated with petroleum ether, b.p. 60-80° C., to give a solid which was crystallized from ethanol to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol, m.p. 266-268° C.
Reaction SMILES: C([NH:14][CH:15]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[P:16]([OH:18])[OH:17])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[P:16]([OH:18])[OH:17]
Reactant: OP(O)C(NC(c1ccccc1)c1ccccc1)c1cccs1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC(c1cccs1)P(O)O

Procedure:
The procedure described in Example 36B was repeated using DL-1-benzhydrylamino-1-(2-thienyl)-methanephosphonous acid instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-1-(thien-2-yl)-methanephosphonous acid, melting point 229°-230°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[C:29](Cl)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[C:29]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:17])=[O:18])=[CH:12][CH:11]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 60 %

Procedure:
A solution of 4-aminophenol (22 mg, 0.2 mmol) in xylenes (2 mL), was treated with 4-chloro-N-(3-chloro-quinoxalin-2-yl)-benzenesulfonamide (35.4 mg, 0.1 mmol) in one portion. The reaction mixture was heated under reflux in an inert atmosphere of nitrogen for 25 h. Reaction progress was monitored by TLC. Upon completion of the reaction, the mixture was cooled, which resulted in compound 5-4 precipitating from the solution as red-yellow crystals. The crystals were filtered and washed with hot methanol (5 mL) and pentane (5×5 mL). Yield 60%, mp=298-301° C. TLC Rf=0.35 (hexanes/EtOAc 1:1). 1H NMR (DMSO-d6, 600 MHz): δ 6.75 (d, J=8.4 Hz, 2H), 7.30 (t, J=7.2 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.69 (d, J=7.8 Hz, 2H), 7.89 (br.s, 1H), 8.11 (d, J=7.8 Hz, 2H), 8.81 (br.s, 1H), 9.30 (br.s, 1H), 12.29 (br.s, 1H). HPLC/MS: [M+H]+ m/z 426. HRMS: Calcd. [M+H]+ m/z 427.0632, Observed 427.0644.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][CH3:11])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([N:10]([CH3:11])[C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:9]=1)=[O:15]
Reactant: CNc1cc(C(C)(C)C)no1
Reactant: CN=C=O
Product: CNC(=O)N(C)c1cc(C(C)(C)C)no1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
A mixture of 3-t-butyl-5-methylaminoisoxazole (2.16 g) and methyl isocyanate (1.04 g) is heated at 80° C. in a sealed tube for 13 hours. Then, methyl isocyanate (0.40 g) is added thereto, and the resultant mixture is heated at 80° C. for 9 hours. The reaction mixture is chromatographed on a column of silica gel, whereby 1,3-dimethyl-3-(3-t-butyl-5-isoxazolyl)-urea (2.56 g) is obtained. The yield is 86.3%. IR: 1700, 1598 cm-1 (CC14).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][C:7](=O)[NH:8][CH:9]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:13]>CN(C)C1C=CC=CC=1>[Cl:13][C:7]1[N:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1
Reactant: CC(C)c1cnc(=O)[nH]c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(C)c1cnc(Cl)nc1

Procedure:
A mixture of 5-isopropylpyrimidin-2(1H)-one (2.1 g, 15.2 mmol), POCl3 (15 ml), and N,N-dimethylaniline (5 drops) was heated at reflux under a nitrogen atmosphere for 2 h. Upon cooling, the majority of the POCl3 was removed under reduced pressure. The residue was poured into ice water and extracted with chloroform (3×20 ml). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated to provide 2-chloro-5-isopropylpyrimidine as a light brown oil, which was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH:5]([C:10]1[CH:11]=[C:12]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([CH:24]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:26]=1)[CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:47])=[O:3])[CH:11]=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:39][CH:38]=3)[CH:13]=2)[CH2:17]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)c1
Temperature: 78 °C

Procedure:
To compound 53a, 2-{5-[1-(3,5-Bis-trifluoromethyl-benzyl)-piperidin-3-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester (106.5 mg, 0.16 mmol) in EtOH (7.9 ml) was added 2M KOH (0.79 ml, 1.6 mmol). The reaction was heated to 78° C. for 1 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (72.3 mg, 67%). 1H NMR (300 MHz, MeOD) δ ppm 0.94 (dd, J=6.22, 2.07 Hz, 6 H) 1.50 (dt, J=13.47, 6.64 Hz, 1 H) 1.67 (ddd, J=13.75, 7.16, 6.97 Hz, 1 H) 1.89-2.04 (m, 3 H) 2.06-2.14 (m, 2 H) 3.11-3.19 (m, 2 H) 3.33-3.43 (m, 1H) 3.51-3.56 (m, 1 H) 3.61-3.65 (m, 1 H) 3.77 (t, J=7.72 Hz, 1 H) 4.49-4.64 (m, 2 H) 7.34 (s, 1 H) 7.55 (d, J=18.09 Hz, 2 H) 7.78 (q, J=8.54 Hz, 4 H) 8.16 (s, 1 H) 8.25 (s, 2 H) Calcd for C33H32F9NO2 (M+H) 645.60, Found 646.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.C(Cl)Cl.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:31])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(C)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
The 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (119 mg, 0.23 mmol) was suspended in 8 ml of methylene chloride containing 10 equivalent of N-methylpiperizine, 1.1 equivalent of HBTU and 4.0 equivalent of triethylamine. The mixture was stirred at room temperature overnight and then evaporated to remove solvents. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-{3-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-isoquinoline-4-carboxylic acid as a fluffy solid (39 mg, 35%). ES-MS calcd for C26H27N3O7 (m/e) 493.5, obsd 494.4 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH3:14]>O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:12])[NH2:14]
Reactant: N
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccccc2c1
Yield: 52 %

Procedure:
A solution of 2-naphthoyl chloride (5.70 g, 29.9 mmol) in tetrahydrofuran (60 ml) was added dropwise to a mixture of 28% aqueous ammonia (20 ml) and tetrahydrofuran (30 ml) with stirring under ice cooling, and the mixture was stirred at room temperature for 4 hrs. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitates were collected by filtration and dried to give 2-carbamoylnaphthalene (2.68 g, 52%) as a colorless solid.
Reaction SMILES: [B:1]([O-:4])([O-:3])[O-:2].[B:5]([O-:8])([O-:7])[O-:6].[B:9]([O-:12])([O-])[O-].[B:13]([O-])([O-])[O-].[Na+:17].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[B:1]1([O-:4])[O:3][B:13]2[O:12][B:9]([O:6][B:5]([O-:8])[O:7]2)[O:2]1.[Na+:17].[Na+:17]
Reactant: [O-]B([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [O-]B1OB2OB([O-])OB(O1)O2
Temperature: 1100 °C
Reaction time: 0.17 h

Procedure:
Sodium tetraborate (Na2B4O7.10H2O), analyzed reagent was dried overnight at 150° C, mixed with the appropriate quantity of dopant ions and homogenized in an electric homogenizer (vibrator) during 10 minutes. The material was then transferred to a platinum crucible and heated at 1100° C for at least 30 minutes, until a clear transparent solution was obtained. The glass matrix loses water and the composition of the matrix is after the heating 35(Na2O).65(B2O3). A drop of the hot melt was allowed to fall directly onto a clean white glazed ceramic surface, into the center of a space ring of 1 mm thickness, and pressed with a second ceramic tile to produce a glass disk of 1 mm thickness and an approximate diameter of 12 mm. The glass is transparent in the ultraviolet and in the visible part of the spectrum.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][N:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)C>[C:1]([C:3](=[C:7]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[CH3:12])=[CH:15][CH:16]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CN(C)c1ccc(N)cc1
Reactant: CSC(SC)=C(C#N)C(N)=O
Solvent: CCO
Product: CSC(Nc1ccc(N(C)C)cc1)=C(C#N)C(N)=O
Temperature: 75 °C
Yield: 91 %

Procedure:
To a solution of 1.00 g (2-cyano-3,3-bis(methylthio)acrylamide) in 25 mL of ethanol was added 0.720 g (1.1 eq.) of N,N-dimethyl-p-phenylenediamine and the reaction was stirred at 75° C. until starting amide was absent as confirmed by HPLC. Once complete (18 hrs), the reaction was brought to room temperature and filtered to obtain 2-cyano-3-((4-(dimethylamino)phenyl)amino)-3-(methylthio)acrylamide as an off white to light yellow powder. The product was allowed to dry under vacuum for 1 hr (1.133 g, 91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13](Cl)[N:12]=[C:11]([O:16][CH2:17][CH2:18][OH:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:12]=[C:11]([O:16][CH2:17][CH2:18][OH:19])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: OCCOc1nc(Cl)nc2c1[nH]c1cc(Br)ccc12
Reactant: C1CNCCN1
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOc1nc(N2CCNCC2)nc2c1[nH]c1cc(Br)ccc12

Procedure:
400 mg (1.17 mmol) 2-(7-bromo-2-chloro-5H-pyrimido[5,4-b]indol-4-yloxy)ethanol and 1.0 g (11.7 mmol) piperazine in 50 ml mesitylene were heated to 150° C. for 5 h. Then, the solvent was removed and the residue was taken up in EtOH and filtrated. Having removed the solvent, 250 mg (55%) of the title substance was obtained. ESI-MS [m/z]: 392, 394[M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH2:15]2)[N:12]=[C:11]([C:30]([F:33])([F:32])[F:31])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][CH3:22])[CH2:15]2)[N:12]=[C:11]([C:30]([F:31])([F:32])[F:33])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1[C@@H]1CCN(CCN(C)C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCN1CC[C@@H](n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.7 %

Procedure:
To a stirred solution of 77 (10 mg, 0.019 mmol) in CH2Cl2 (0.38 mL) was added TFA (0.073 mL, 0.951 mmol). The resulting solution was allowed to stir at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column chromatography with gradient of methanol (5-30%) in dichloromethane to afford 78 (10 mg, 80%) as a white solid. 1H NMR (DMSO-d6) δ(ppm): 9.11 (t, J=5.1 Hz, 1H), 7.38 (s, 1H), 7.27-7.19 (m, 2H), 7.00 (d, J=7.8 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.83 (qi, J=9.0 Hz, 1H), 4.41 (q, J=6.1 Hz, 2H), 3.81 (s, 3H), 3.20-3.16 (m, 1H), 2.96-2.92 (m, 2H), 2.80-2.68 (m, 4H), 2.53 (d, J=2.2 Hz, 3H), 2.32-2.17 (m, 3H). LRMS (ESI): calc. 425.2; found 426.1 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([O:17][C:18](=[O:33])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:33])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
Methyl bromoacetate (128.5 mg, 0.84 mmol) potassium iodide (11.7 mg) and potassium carbonate (193.5 mg, 1.4 mmol) were added to a solution of (4′-hydroxy-biphenyl-4-yl)-carbamic acid tert-butyl ester (0.2 g, 0.70 mmol), prepared in the previous step, in 15 mL of THF and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted multiple times with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent removed under reduced pressure. Purification of the residue on silica gel using 20% ethyl acetate-hexane as the eluent gave (4′-tert-butoxycarbonylamino-biphenyl-4-yloxy)-acetic acid methyl ester (208 mg, 80%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:11])[CH2:24][CH2:25]2)=[N:27]1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)CC2C=CC(OC)=CC=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[Cl:26][C:27]1[C:33]([N:34]2[CH2:37][CH:36]([N:38]3[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH2:35]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH2:29].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:26][C:27]1[C:33]([N:34]2[CH2:35][CH:36]([N:38]3[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]3)[CH2:37]2)=[CH:32][C:31]([O:45][CH:46]([F:48])[F:47])=[CH:30][C:28]=1[NH:29][C:2]1[N:7]=[C:6]([NH:8][CH:18]2[CH2:19][CH2:20]2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: CN1CCN(C2CN(c3cc(OC(F)F)cc(N)c3Cl)C2)CC1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CN1CCN(C2CN(c3cc(OC(F)F)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)C2)CC1
Temperature: 105 °C
Yield: 75.9 %

Procedure:
2-Chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9) (120 mg, 0.338 mmol), 2-chloro-5-(difluoromethoxy)-3-(3-(4-methylpiperazin-1-yl)azetidin-1-yl)aniline (129 mg, 0.372 mmol), palladium(ii) acetate (22.78 mg, 0.101 mmol), XANTPHOS (19.57 mg, 0.034 mmol), DPPF (18.75 mg, 0.034 mmol) and CESIUM CARBONATE (220 mg, 0.676 mmol) were suspended in Dioxane (3382 μl) at rt. The reaction vessel was evacuated and purged with N2 (4 times) and then heated to 105° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc, filtered through celite and concentrated. Column chromatography (40 g SiO2, 0 to 10% CH3OH—CH2Cl2 gradient elution) afforded the expected product (139.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].ClC1C(F)=C(B(O)O)C=CC=1>CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:24]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH3:20])[N:22]=[CH:23]2)[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[C:3]([F:19])=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]cnc1C
Agent: CCOC(=O)c1ncn(-c2cccc(Cl)c2F)c1C
Agent: OB(O)c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1c(C)ncn1-c1cccc(Cl)c1F
Reaction time: 20 h
Yield: 2 %

Procedure:
Ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate: Using a modified procedure of Sreedhar. (Reference: Sreedhar, B., Synthesis, 795 (2008)). To a suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (0.530 g, 3.44 mmol) and (3-chloro-2-fluorophenyl)boronic acid (0.500 g, 2.87 mmol) in MeOH (5.74 mL) was added cuprous oxide (0.041 g, 0.287 mmol). The resulting purple suspension was stirred vigorously under an atmosphere of air (drying tube used). After 20 h, the reaction mixture was filtered to remove the solids and the clear blue filtrate was concentrated to give a blue solid. The blue solid was suspended in DCM and filtered to remove the solids and the blue filtrate was concentrated to give a pale blue solid weighing 0.187 g. Purification by normal phase chromatography gave ethyl 1-(3-chloro-2-fluorophenyl)-4-methyl-1H-imidazole-5-carboxylate (0.0187 g, 2%) as a clear, colorless residue and ethyl 1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carboxylate (Intermediate 24A) (0.0079 g, 1%) as a clear, colorless residue. MS(ESI) m/z: 283.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCOCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[S:26])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1cccc(NC(=O)C(F)(F)F)c1Br
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COc1cccc(NC(=S)C(F)(F)F)c1Br
Temperature: 25 °C

Procedure:
A solution of N-(2-bromo-3-methoxyphenyl)-2,2,2-trifluoroacetamide (C24) (776 mg, 2.6 mmol) and Lawesson's reagent (1.07 g, 2.6 mmol) in 1,4-dioxane (13 mL) was heated to 135° C. overnight. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. Purification via silica get chromatography (Gradient: 0% to 20% ethyl acetate in heptanes) afforded the title compound as an oil. Yield: 839 mg, 2.60 mmol, quantitative. LCMS m/z 314.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 6.92 (dd, J=8.3, 1.1 Hz, 1H), 7.39 (dd, J=8.4, 8.3 Hz, 1H), 8.28 (dd, J=8.2, 0.8 Hz, 1H), 9.75 (br s, 1H).