Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 42.95 g (0.36 mol) of propargyl bromide in 30 ml of dimethylformamide was added dropwise to a suspension of 50 g (0.26 mol) of 2-bromo-5-fluoro-phenol and 55 g of potassium carbonate in 300 ml of dimethylformamide and the mixture was subsequently stirred at room temperature for two hours. The mixture was poured on to 1500 ml of ice-water and extracted three times with 600 ml of dichloromethane each time. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). 58 g (97%) of 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene were obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([NH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(C)(C)NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(1-amino-1-methylethyl)benzoate (200 mg) and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), methanesulfonyl chloride (88 μL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 2 hr. After completion of the reaction, the solvent was evaporated, 0.5N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (252 mg).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH:9]=[CH2:10])[CH2:6][O:5][CH2:4]1)[CH3:2].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[C:31]1([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:42]=[C:41]([C:43]3[CH:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]=[CH:47][CH:48]=3)[N:40]=[C:39]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57](Br)[CH:56]=3)[N:38]=2)[CH:32]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:31]1([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[N:42]=[C:41]([C:43]3[CH:44]=[C:45]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH:46]=[CH:47][CH:48]=3)[N:40]=[C:39]([C:55]3[CH:56]=[CH:57][CH:58]=[C:59]([CH2:10][CH2:9][O:8][CH2:7][C:3]4([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]4)[CH:60]=3)[N:38]=2)[CH:32]=1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Reactant: C=COCC1(CC)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1(COCCc2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)COC1
Temperature: 20 °C

Procedure:
13.1 g of 3-ethyl-3-vinyloxymethyloxetane and 11.3 g of 9-BBN dimer (9-borabicyclo(3.3.1)nonane dimer) are dissolved in 200 ml of toluene at room temperature under protective gas and stirred for 20° C. During the reaction, the suspension of 9BBN slowly dissolves. 50 g of 2,4-bis-biphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 50 ml of a 1M NaOH solution are subsequently added to the reaction solution. The reaction mixture is carefully degassed, and 200 mg of tetrakistriphenylphosphinepalladium are added, and the mixture is heated under reflux for 20 hours. The solution is cooled to room temperature. The phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo.
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 97 %

Procedure:
To a solution of Example 39A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.70 g, 97%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 (m, 6 H) 1.09 (m, 2 H) 1.52 (m, 4 H) 1.99 (m, 2 H) 7.35 (m, 5 H).
Reaction SMILES: Cl.[CH3:2][NH2:3].C[O:5][C:6]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([NH:17][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=4)[C:21]([F:36])=[CH:20][N:19]=3)[CH:15]=[CH:16][C:10]=2[O:9]1)=O>>[CH3:2][NH:3][C:6]([CH:8]1[CH2:12][C:11]2[CH:13]=[C:14]([NH:17][C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:35])[F:33])[CH:26]=4)[C:21]([F:36])=[CH:20][N:19]=3)[CH:15]=[CH:16][C:10]=2[O:9]1)=[O:5]
Reactant: CN
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cccc(OC(F)(F)F)c4)n3)ccc2O1
Agent: Cl
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cccc(OC(F)(F)F)c4)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2-(N-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl]-2,4-pyrimidinediamine, the reaction of methyl amine Hydrogen Chloride with (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine gave (±)-N2-[2,3-dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. LCMS: purity: 94%; MS (m/e): 464 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:14])[CH3:13])[CH:2]([CH3:4])[CH3:3].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([O:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)c1ccccc1OCC(C)C
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C)c1ccccc1OCC(C)C
Reaction time: 0.25 h

Procedure:
A solution of commercially available 1-(2-isobutoxyphenyl)ethanone (10.0 g, 56.5 mmol) in THF (30 mL) was added dropwise to a stirred solution of lithium hexamethylsilylamide (1M in hexanes, 62 mL) in THF (200 mL) over a period of 30 min at 0° C. The resulting solution was stirred for an additional 15 min, and a solution of chlorotrimethylsilane (7.1 mL) in THF (8 mL) was added. The reaction mixture was stirred for 4 hours at room temperature. The mixture was concentrated. To the residue was added dichloromethane (60 mL), the mixture was filtered. The filtrate was concentrated to give (1-(2-isobutoxyphenyl)vinyloxy)trimethylsilane, that was submitted to the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1>C(O)(=O)C.C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][N:25]([C:27]2[CH:33]=[CH:32][C:30]([NH:31][C:2]3[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:29][C:28]=2[O:34][CH3:35])[CH:26]=1
Reactant: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(Cl)cc2)ccc1-n1cnc(Cl)c1
Temperature: 75 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (98 mg, 0.318 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (71.1 mg, 0.318 mmol) in acetic acid (1.000 mL) and THF (1 mL). The reaction mixture was heated at 75° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (17.2 mg, 0.028 mmol, 8.70% yield). LC-MS (M+H)+=495.1. 1H NMR (500 MHz, CDCl3) δ ppm 11.80 (1H, s), 7.61-7.72 (1H, m), 7.34-7.42 (2H, m), 7.27-7.33 (2H, m), 7.21 (2H, d, J=8.5 Hz), 7.16 (1H, d, J=9.2 Hz), 7.06 (1H, d, J=1.5 Hz), 4.30-4.41 (1H, m), 3.82 (6H, s), 3.48 (1H, br. s.), 3.31-3.39 (2H, m), 3.18-3.27 (1H, m), 2.58-2.80 (2H, m), 2.14-2.29 (1H, m).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[CH:9][C:8]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CN(C)C=O.O>[N+:17]([C:6]1[CH:7]=[C:8]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:9]=[CH:10][C:5]=1[C:2]#[N:3])([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(S(F)(F)(F)(F)F)ccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 14 °C
Reaction time: 1.25 h
Yield: 95.1 %

Procedure:
Copper (I) cyanide (5.05 g) was added to a stirred solution of 4-bromo-3-nitro-phenylsulphur pentafluoride (18.5 g) in N,N-dimethylformamide and heated at 14° C. for 4 hours. A mixture of ferric chloride (20.0 g),concentrated hydrochloric acid and water was added at 105° C. and heating continued for 1.25 hours. The cooled mixture was diluted with water, extracted (ether) and the organic phase washed (water), dried (magnesium sulphate) and evaporated to give 2-nitro-4-pentafluorosulphanylbenzonitrile (14.7 g), m.p.57-59° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:12][C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:17]=4[O:16][CH2:15][CH2:14]3)[C:6]=2[CH2:5][CH2:4]1)[CH3:2].[NH2:27][C:28]1[C:33]([S:34]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]2)(=[O:36])=[O:35])=[CH:32][C:31](Br)=[CH:30][N:29]=1>>[NH2:42][C@@H:39]1[CH2:40][CH2:41][N:37]([S:34]([C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[C:31]([C:21]3[CH:22]=[CH:23][C:17]4[O:16][CH2:15][CH2:14][N:13]([C:7]5[C:6]6[CH2:5][CH2:4][C@H:3]([CH2:1][CH3:2])[CH2:12][C:11]=6[N:10]=[CH:9][N:8]=5)[CH2:19][C:18]=4[CH:20]=3)[CH:32]=2)(=[O:35])=[O:36])[CH2:38]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CC[C@@H](N)C5)c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and 1,1-dimethylethyl {(3R)-1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 25) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.53 (d, 1H), 8.33 (s, 1H), 7.99 (d, 1H), 7.57 (d, 1H), 7.44 (dd, 1H), 7.01 (d, 1H), 6.75 (brs, 2H), 4.70 (dd, 2H), 4.36 (m, 1H), 4.24 (m, 1H), 3.86 (m, 2H), 3.36 (m, 2H), 3.26 (m, 2H), 2.87, 2.83 (m, dd, 3H), 2.27 (dd, 1H), 1.89 (m, 3H), 1.68 (m, 1H), 1.52 (m, 1H), 1.37 (m, 2H), 1.11 (m, 1H), 0.94 (t, 3H); MS (EI) for C28H35N7O3S: 550 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:28][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][CH:27]=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:24]=1
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1ccc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2c1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (75 mg) and 6-methoxy-2-naphthol (174 mg) obtained in Example 1 were mixed and stirred at 180° C. for 30 minutes, and the reaction mixture was then purified by thin layer chromatography on silica gel (eluting with hexane/acetone (2/1)) to obtain 71 mg of the title compound (yield: 59%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[O:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]=1[NH2:32]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:32][C:22]4[N:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:24][O:25][C:21]=4[CH3:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: CC1=C(N)N(c2ccccc2)CO1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CC1=C(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)N(c2ccccc2)CO1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 5-methyl-3-phenyl-4-oxazolylamine gave N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.80-7.65 (m, 2H), 7.45 (bd, 1H), 7.20 (m, 1H), 7.00 (m, 1H), 6.65 (bd, 1H), 4.20 (s, 4H), 2.35 (s, 3H); LCMS: ret. time: 20.61 min.; purity: 78%; MS (m/e): 420 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[C:6]([OH:17])[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[H][H]>[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:18])=[C:6]([OH:17])[C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCOCC2)c1O
Yield: 94.6 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 6-chloro-2-hydroxy-1-(4-morpholinylsulfonyl)-3-nitrobenzene (210 mg, 0.65 mmol) was reduced with hydrogen and Pd/C (100 mg) to form the desired product (180 mg, 95%). 1H NMR (MeOD-d4): δ 6.28 (mn, 2H), 3.68 (t, 4H), 3.30 (t, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[Cl-].[NH4+]>CO.O.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1cc(I)ccc1Cl
Temperature: 50 °C

Procedure:
To 1-chloro-4-iodo-2-nitrobenzene (1.27 g, 4.49 mmol) in methanol (20 ml) was added iron powder (1.25 g, 22 mmol) and the reaction heated to 50° C. A solution of ammonium chloride (1.92 g, 36 mmol) in water (10 ml) was added slowly and the reaction heated to 70° C. overnight. Reaction was cooled, filtered through celite, washed with methanol and solvent reduced in vacuo. The residue was purified by chromatography on silica gel (gradient of hexane to 10% ethyl acetate in hexane) to afford the title compound. MS (ES+) m/e 254 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-])=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].C([O-])=O.[NH4+]>CO.O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=[N+]([O-])CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 1-chloro-4-(4-(2-nitroethyl)phenoxy)-2-(trifluoromethyl)benzene (21 g, 60.7 mmol) and ammonium formate (30.6 g, 486 mmol) in methanol (250 mL) and water (250 mL), was added zinc powder (15.89 g, 243 mmol). The reaction mixture was stirred at 80° C. for 2 h, filtered through a glass grit and washed with methanol. The filtrate was concentrated and the residue was extracted with DCM (200 mL), and then washed with sat. NaHCO3 (100 mL), brine, and dried over anhydrous Na2SO4 and concentrated. Purification via FC (DCM/CH3OH=100/8) afforded the title compound (7.0 g) as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic Acid Tert-butyl Ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic Acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To acetone 40 mL solution of 4-bromo-2-nitrobenzoic acid 4.0 g were added potassium carbonate 3.4 g and dimethylsulfate 2.3 mL at room temperature, and it was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution,1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give methyl 4-bromo-2-nitrobenzoate 4.1 g of white solid.
Reaction SMILES: [CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][CH:12]=3)[C:8]3[CH:30]=[C:31]([C:35]4[N:39]([CH3:40])[C:38]5[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=5[N:36]=4)[CH:32]=[C:33]([CH3:34])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:15][CH:16]=3)[C:8]3[CH:30]=[C:31]([C:35]4[N:39]([CH3:40])[C:38]5[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=5[N:36]=4)[CH:32]=[C:33]([CH3:34])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[CH2:28]([P:30](C#N)([CH2:32][CH3:33])=[O:31])[CH3:29]>CN(C)C=O>[CH2:28]([P:30]([NH:3][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:5]=1)=[NH:2])([CH2:32][CH3:33])=[O:31])[CH3:29]
Reactant: CCP(=O)(C#N)CC
Reactant: COC(=O)CCc1ccc(-c2nc(-c3ccc(C(=N)N)cc3)cn2C)cc1
Solvent: CN(C)C=O
Product: CCP(=O)(CC)NC(=N)c1ccc(-c2cn(C)c(-c3ccc(CCC(=O)OC)cc3)n2)cc1

Procedure:
Prepared by reacting 4-(4-amidino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-1-methyl-imidazole with diethylphosphorylcyanide in dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]#[N:29])[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.[F:30]C1C(CC2N3N=C(C4C=NNC=4)C=CC3=NC=2)=C(F)C=C2C=1C=CC=N2>>[F:30][C:4]1[C:3]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22]4[CH:23]=[N:24][N:25]([CH2:27][C:28]#[N:29])[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[C:2]([F:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(-c3cn[nH]c3)nn12
Reactant: N#CCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Product: N#CCn1cc(-c2ccc3ncc(Cc4c(F)cc5ncccc5c4F)n3n2)cn1

Procedure:
The title compound was prepared in analogy to the compound of Example 176 using 5,7-difluoro-6-[6-(1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 263) instead of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (tR 3.28 min (conditions 13), MH+=402).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[ClH:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:12])=[CH:4][C:3]=1[S:8]([N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)[CH2:18][CH2:19]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: COc1cc2c(cc1OC)CN(CC1CCNCC1)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CN(CC1CCN(S(=O)(=O)c3cc(Cl)ccc3Cl)CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
2-Chlorobenzene-1-sulfonyl chloride (301.9 mg, 1.43 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (472 mg, 1.3 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) in CH2Cl2 (25 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×30 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (2 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.6 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (406 mg, 63%).