Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][OH:36])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44].[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:20][N:19]=4)=[C:11]4[S:30][CH:31]([CH3:33])[CH2:32][C:9]([C:10]=34)=[C:8]2[CH2:34][CH2:35][O:36][CH:42]([CH2:46][CH3:47])[C:43]([OH:45])=[O:44])=[CH:4][CH:3]=1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Reactant: CCC(Br)C(=O)O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(OCCc1c2c3c(c(OCc4ccc(-c5ccccc5)cn4)ccc3n1Cc1ccc(Cl)cc1)SC(C)C2)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of product from Step 6 (130 mg, 0.23 mmol) in THF (2 mL) there was added 97% NaH (23 mg, 1 mmol) and the mixture was stirred at r.t. for 15 min. There was added a solution of 2-bromobutyric acid (84 mg, 0.5 mmol) in THF (1.5 mL) and the mixture was refluxed for 20 hours. After cooling, there was added more NaH (46 mg) and 2-bromobutyric acid (170 mg) and the mixture was refluxed for a further 24 hours. The cooled mixture was diluted with H2O, made strongly basic with 1N aq NaOH, and extracted twice with Et2O. The aqueous fraction was then acidified with 1N HCl and extracted 3× with EtOAc. The crude product thus obtained was purified by esterification with ethereal diazomethane and the resulting ester chromatographed on preparative TLC silica gel plates, eluting with a 1:4 mixture of EtOAc and toluene. After extraction of the silica with EtOAc, the purified ester (54 mg) was hydrolyzed. It was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and there was added 1M aq LiOH (0.8 mL). The mixture was heated to 50° C. for 30 min., then the organic solvents were evaporated. The residue was diluted with H2O (4 mL) and centrifuged. The supernatant was decanted and the insoluble lithium salt was suspended in H2O (4 mL). The mixture was acidified with 1N aq HCl, stirred vigorously and filtered to afford the title compound as a light yellow solid; m.p. 159°-162° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13]C(=O)[N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:35]([F:38])([F:37])[F:36])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42](B(O)O)[CH:41]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[N:40][C:49]6[C:44]([CH:43]=5)=[CH:45][CH:46]=[CH:47][CH:48]=6)[CH:3]=4)[N:8]=[CH:7][C:6]=3[CH2:12][OH:13])=[CH:17][C:18]=2[C:35]([F:38])([F:36])[F:37])[CH2:23][CH2:24]1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of tert-butyl 4-(4-(9-chloro-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (56 mg, 0.1 mmol) and quinolin-3-ylboronic acid (25 mg, 0.15 mmol) in 1,4-dioxane (1 mL) at room temperature was added bischloroditriphenyl phosphine palladium (4 mg, 0.005 mmol), tert-butyl Xphos (4 mg, 0.01 mmol), and Na2CO3(0.3 mL, 0.3 mmol). The resultant solution was heated to 100° C. for 4 h and then allowed to cool to room temperature, filtered through celite, and washed with EtOAc (3×10 mL). After removal of solvent in vacuo, the residue was purified by flash column chromatography to afford the title compound (35 mg, 55%). LC-MS: (M+H)=630.30
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=1)=[O:9]
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1nnc(C(F)(F)F)s1)c1cc(Br)ccc1O
Yield: 80.2 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C@H:10]([NH:16][C:17](=O)[O:18]C(C)(C)C)[CH2:11][O:12][CH:13]([F:15])[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:26](F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:10]([CH2:11][O:12][CH:13]([F:15])[F:14])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])(=[O:18])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Tert-Butyl {(1R)-2-(benzylamino)-1-[(difluoromethoxy)methyl]-2-oxoethyl}carbamate (340 mg, 0.987 mmol) was stirred with trifluoroacetic acid (2.25 mL) and dichloromethane (2.5 mL) in an ice bath for an hour. The reaction mixture was concentrated, stirred with acetic anhydride-pyridine (1:1, 5.8 mL) at room temperature for 30 minutes and then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, 0.5N HCl and brine again. The organic layer was dried, concentrated, and triturated with diethyl ether to give (2R)-2-(acetylamino)-N-benzyl-3-(difluoromethoxy)propanamide (230.5 mg, 77.2%) as a white solid. Mp: 186.9° C. 1H NMR (300 MHz, DMSO-d6): (ppm) 8.60 (t, 1H), 8.30 (d, 1H), 7.28-7.45 (m, 5H), 6.67 (wt, 1H), 4.58 (m, 1H), 4.40 (d, 2H), 3.98 (d, 2H) and 1.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24]([OH:26])=[O:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39]O>>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][O:25][C:24]([C:6]1[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=2)[C:8](=[O:12])[C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)=[O:26]
Reactant: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reactant: OCc1ccccn1
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)OCc3ccccn3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid and 2-pyridinemethanol.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]>C(#N)C>[CH3:18][O:19][C:20]([C:22]1[O:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([O:30][C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:33][CH:32]=3)=[C:24]2[CH:23]=1)=[O:21]
Reactant: COC(=O)c1cc2c(Oc3ccc(N)cc3)ccnc2o1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2o1

Procedure:
After adding toluene (1 ml), acetonitrile (0.5 ml) and 4-fluorophenyl isocyanate (0.02 ml) to 4-(4-aminophenoxy)furo[2,3-b]pyridine-2-carboxylic acid methyl ester (28 mg), the mixture was heated to reflux for 30 minutes. After cooling, the precipitated crystals were filtered off and washed with toluene to obtain the title compound (24 mg) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C:41](O)(=[O:44])[CH:42]=[CH2:43].N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[C:25]([NH:28][C:29]([C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[C:41](=[O:44])[CH:42]=[CH2:43])=[O:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C=CC(=O)O
Reactant: COCCOc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2cc1NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)N1CCC[C@H]1C(=O)Nc1cc2c(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)ncnc2cc1OCCOC
Temperature: 0 °C
Yield: 17 %

Procedure:
288 mg of (2S)-pyrrolidine-2-carboxylic acid {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-7-(2-methoxyethoxy)-quinazolin-6-yl}-amide as a starting material was dissolved in 10 ml of THF, and cooled to 0° C. The solution was reacted with 0.07 ml of acrylic acid, 0.17 ml of pyridine and 0.29 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at 0° C. for 30 mins and at room temperature for 2 hours. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=30:1) to obtain the title compound (52 mg, 17%).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]1[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=1)=[O:15])([CH3:10])[CH3:9].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br-:1].[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N+:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:21]([NH2:22])=[N:20][C:19]([NH2:23])=[C:18]([Cl:24])[N:17]=2)=[O:15])([CH3:9])[CH3:10])=[O:41])=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
A solution of (5-amino-pentyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate O) (1.0 g, 2.35 mmol), 4-benzyloxy phenyl acetic acid (0.57 g, 2.35 mmol), N-methylmorpholine (1.0 mL, 9.09 mmol), DCC (0.49 g, 2.35 mmol) and HOBt (0.32 g, 2.36 mmol) in DMF (20 mL) is stirred at RT for 1 h. The reaction mixture is concentrated in vacuo, and the residue is purified by column chromatography (basic alumina, 0-4% methanol in DCM) to afford a brown solid which is crystallised from methanol and EtOAc to afford the title compound. M+ 568.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([O:33]CC5C=CC=CC=5)=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(O)cc4)ccc(F)c32)cc1
Reaction time: 1 h

Procedure:
(1S,2S)-2-{4-[(R)-4-(4-Benzyloxy-phenoxy)-7-fluoro-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 6, 0.76 g, 1.3 mmol) is dissolved in 1:1 MeOH/ethyl acetate (20 mL) and hydrogenated at 2 Bar for 1 hour using 10% palladium on carbon as the catalyst. The mixture is filtered through CELITE filter aid and the solvent removed under vacuum the title compound. (Yield 0.60 g). LC (METHOD 6): tR=0.64 min; Mass spectrum (ES+): m/z=449 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:35]([NH:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([O:26][CH3:25])=[O:37])=[O:36])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added methyl-2-isocyanatobenzoate (216 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 239 mg (69.5%) of the desired product as a solid.
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH3:16][Si:17](Cl)([CH2:19][CH2:20][Si:21](Cl)([CH3:23])[CH3:22])[CH3:18]>O1CCCC1>[F:8][C:9]1[CH:10]=[C:11]([N:12]2[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:17]2([CH3:18])[CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(F)c1
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of freshly distilled diisopropylamine (22.9 mL) in dry tetrahydrofuran (175 mL) at -78° C. under N2 is treated with n-butylithium (1.6 M in hexanes, 109 mL) dropwise over 15 minutes, and the resulting mixture is stirred at -78° C. for 45 minutes and is then added over ten minutes via cannula to a solution of 3-fluoroaniline (8.00 mL) in dry tetrahydrofuran (166 mL) at -78° C. under N2. The resulting reaction mixture is stirred at -78° C. for 50 minutes and is then treated with a solution of 1,1,4,4-tetramethyl-1,4-dichlorodisilethylene (18.3 g) in dry tetrahydrofuran (85 mL). The mixture is allowed to slowly warm to ambient temperature over four hours with stirring and is then washed with water (2×200 mL) and saline (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.12, 6.65, 6.58, 0.86, 0.24 δ.
Reaction SMILES: CN(C=O)C.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>C(OCC)(=O)C>[N:22]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH2:17][OH:18])[CH:16]=1)=[N+:23]=[N-:24]
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1CO
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc([N+](=O)[O-])c(CO)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
DMF (7.5 mL) was added to (5-(3-chloropropoxy)-2-nitrophenyl)methanol (635 mg, 0.00258 moles) and sodium azide (252 mg, 0.00387 moles) in a flask, and the resulting mixture was heated to 70° C. and stirred overnight. The reaction was diluted in ethyl acetate (100 mL) and washed twice with water (75 mL each) and once with brine (75 mL). The organic layer was dried with anhydrous magnesium sulfate, which was filtered out. The filtrate was concentrated on a rotary evaporator and dried in vacuo overnight to yield (5-(3-azidopropoxy)-2-nitrophenyl)methanol as a yellow solid (yield 88%). H NMR (400 MHz, CD2Cl2) δ 8.16 (d, J=9.1 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 6.91 (dd, J=9.1, 2.8 Hz, 1H), 4.98 (s, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.53 (t, J=6.6 Hz, 2H), 2.12-2.06 (m, 2H). 13C-NMR (100 MHz, CD2Cl2) δ 163.99, 141.22, 128.43, 114.97, 113.93, 66.15, 63.26, 48.68, 29.13 HRMS m/z: calculated for C10H12N4O4 [M+H]+, 253.0931. found, 253.0939.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].[NH2:19][C:20]1[CH:25]=[C:24](Cl)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]>O>[NH2:19][C:20]1[CH:25]=[C:24]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:23]=[CH:22][C:21]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A solution of 7.5 g. of 2-benzyloxyethanol in 30 ml. of dimethylformamide is treated with 1.2 g. of sodium hydride. When the mixture is homogeneous, 3.5 g. of 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated at 110°-120° for 4 hours. The mixture is cooled, diluted with water and extracted with benzene. The crude product is treated with charcoal and isolated by precipitation with cyclohexane to afford 2-amino-1-nitro-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: N1SC=C2C=C(N)C=CC=12.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[S:26]([C:30]1[CH:35]=[CH:34][C:33]([NH-:36])=[CH:32][CH:31]=1)(=[O:29])(=[O:28])[NH2:27]>>[S:26]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:23]([C:20]2[CH:21]=[N:22][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:18][CH:19]=2)=[O:25])=[CH:34][CH:35]=1)(=[O:28])(=[O:29])[NH2:27]
Reactant: [NH-]c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: Nc1ccc2nscc2c1
Product: NS(=O)(=O)c1ccc(NC(=O)c2cnc(-c3ccccc3)nc2)cc1

Procedure:
Following procedures similar to those of Example 8 but substituting 4-amino-benzenesulfonamide (0.3 mmol) for 2,2-dioxo-2,3-dihydro-1H-2lamda*6*-benzo[c]isothiazol-5-ylamine, there is prepared 2-phenyl-pyrimidine-5-carboxylic acid (4-sulfamoyl-phenyl-amide as a solid. MS: 355 (M+H). IC50=5 nM.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17].N1C=CC=CC=1>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Cl)ccc1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A mixture of 2-amino-5-chloroanisole (157 mg, 1 mmol), thiophene-2-sulfonyl chloride (183 mg, 1 mmol), and pyridine (0.25 mL, 3 mmol) in methylene chloride (3 mL) was stirred at room temperature for 16 hours. The mixture was then partitioned between methylene chloride and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 290 mg (96%) of the title compound. MS (ESI) m/e 304 (M+H)+.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.[Li].O>C(OCC)C>[CH:14]1([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:5]2[SiH:2]([CH3:4])[CH3:3])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: C1=Cc2ccccc2C1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Agent: [Li]
Solvent: CCOCC
Solvent: O
Product: C[SiH](C)C1=Cc2ccccc2C1C1C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Chloro-2-indenyldimethylsilane (4.95 g, 0.023 mol.) according to Example 1 was dissolved in 20 ml of diethyl ether. The solution was cooled to 0° C., and a solution of lithium indene (1.94 g, 0.022 mol.) in 25 ml of diethyl ether was added dropwise. The mixture was stirred for 2 hours at 25° C. and then heated to reflux. For working up, 60 ml of water were added and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the light-yellow oil that remained was purified by means of column chromatography. 3.23 g (47%) of 1-indenyl-2-indenyl-dimethylsilane were obtained in the form of a colorless oil which crystallized in the refrigerator at 4° C. M.p.: 45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]23[CH2:15][CH:14]2[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]3)[CH:7]=1.[F:18][C:19]([F:32])([F:31])[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[F:17][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([F:32])([F:31])[F:18])=[CH:27][N:26]=2)=[O:29])=[CH:7][C:6]=1[C:8]12[CH2:15][CH:14]1[CH2:13][O:12][CH2:11][C:10](=[S:16])[NH:9]2
Reactant: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(OCC(F)(F)F)cn1

Procedure:
Prepared in an analogous manner as described for intermediate B14A from (1SR,7RS)-1-(5-amino-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13A) (87 mg, 0.34 mmol) and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [CAS-no 881409-53-6; described in example 49] (80 mg, 0.36 mmol). The title compound was obtained as a light yellow solid (143 mg, 87%). MS (ISP): m/z=456.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)C[C@H](N)CO
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 125 °C
Yield: 82.9 %

Procedure:
A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (0.85 g, 3.10 mmol), (S)-2-amino-4-methylpentan-1-ol (0.544 g, 4.64 mmol) and diisopropylethylamine (1.082 mL, 6.19 mmol) in DMA (Volume: 10 mL) was heated to 125° C. for 1.25 hr. After cooling to rt, ice cold water (˜60 ml) was added to the rapidly stirring reaction mixture. The reaction mixture was stirred for 15 minutes, was sonicated for 15 minutes and was stirred and additional 15 minutes. The resulting suspension was filtered and the filter cake was washed with water. Drying afforded (S)-6-bromo-4-(1-hydroxy-4-methylpentan-2-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (0.94 g, 2.57 mmol, 83% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (d, J=6.4 Hz, 3H) 0.91 (d, J=6.4 Hz, 3 H) 1.40 (m, 1 H) 1.56-1.60 (m, 1 H) 1.61-1.70 (m, 1 H) 3.39-3.48 (m, 1 H) 3.58 (m, 1 H) 4.08-4.17 (m, 1 H) 4.98 (dd, J=6.2, 4.8 Hz, 1 H) 7.04 (d, J=1.5 Hz, 1 H) 7.84 (d, J=1.8 Hz, 1 H) 8.21 (s, 1 H) 10.59 (d, J=8.6 Hz, 1 H). MS (ES+) m/z: 354.9, 356.9 (M+H); LC retention time: 2.517 min (analytical HPLC Method B).