Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:23])[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=3)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:4]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 132 from 4-chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 130, step 7) with methyl-5-chloropyrazine-2-carboxylate [CAS Reg. No. 33332-25-1]. MS (m/e)=502.1 [MH+].
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][CH2:13][C:14]1[CH:43]=[CH:42][C:17]([CH2:18][N:19]([CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47](O)=[O:48].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:44][C:45]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])(=[O:21])=[O:22])[CH:32]2[CH2:41][C:40]3[N:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]2)=[CH:42][CH:43]=1)=[O:48]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)c1c(Cl)cncc1Cl
Yield: 39.4 %

Procedure:
Using the EDCI coupling general procedure F: Reaction of N-(4-Aminomethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-7-yl)-benzenesulfonamide (75 mg, 0.17 mmol), 3,5-dichloroisonicotinic acid (75%, 55 mg, 0.22 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), 4-methyl morpholine (100 uL, 0.89 mmol), and EDCI (32 mg, 0.17 mmol) for two days at 50° C. followed by column chromatography on silica gel (1:1:98 MeOH—NH4OH—CH2Cl2) gave the title compound (42 mg, 40%) as a yellow foam.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:10]([O:28]CC2C=CC=CC=2)=[N:9]1)C1C=CC=CC=1.C(N1C(=O)C(C2C=CN=CC=2)=C(C2C=CC(Cl)=CC=2)C(OCC2C=CC=CC=2)=N1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[C:13](=[O:14])[NH:8][NH:9][C:10](=[O:28])[C:11]=2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c(-c2ccncc2)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: O=c1c(-c2ccncc2)c(-c2ccc(Cl)cc2)c(OCc2ccccc2)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH][nH]c(=O)c(-c2ccc(Cl)cc2)c1-c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-benzyl-6-(benzyloxy)-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazin-3(2H)-one and 2-benzyl-6-(benzyloxy)-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (2.8 g, 5.8 mmol) in toluene (35 ml) was added AlCl3 (3.1 g, 23.2 mmol). After stirring at 80° C. for 30 min. After this time, the reaction mixture was cooled to RT and 40 ml water was added. A precipitate formed which was subsequently collected by filtration. The title compound, 4-(4-chlorophenyl)-5-(pyridin-4-yl)-1,2-dihydropyridazine-3,6-dione was obtained as a yellow powder (1.1 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[C:37]([CH3:38])=[CH:36][C:35]([Cl:39])=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2.C(Cl)Cl.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CS(C)=O.O.C1COCC1>[Cl:39][C:35]1[CH:36]=[C:37]([CH3:38])[C:28]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:26])[CH:8]=2)=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: Cc1cc(Cl)c2ncccc2c1Br
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Cl)c2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 120 °C

Procedure:
A mixture of 6-(3,5-Dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (100.0, 0.282 mmol) and 5-bromo-8-chloro-6-methylquinoline (72.2 mg, 0.282 mmol) was treated with PdCl2dppf.CH2Cl2 (20.9 mg, 0.028 mmol) in the presence of 1,8-Diazabicycloundec-7-ene (DBU, 204.0 mg, 1.34 mmol, 4.76 equiv) in DMSO (0.2 mL) and water (0.2 mL). The reaction mixture was heated at 120° C. in oil bath. The reaction mixture was diluted with THF (3 mL) and purified by Gilson preparative HPLC to give 4-(8-chloro-6-methylquinolin-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C@@H:18]2[CH2:20][O:19]2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C@H:15]([C@@H:18]([OH:19])[CH2:20][S:3][CH2:1][CH3:2])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H]2CO2)C1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
Ethanethiol (312 μL, 4.2 mmol) was dissolved in THF (1.0 mL), and the mixture was cooled to 0° C. NaH (50.6 mg, 2.1 mmol) was slowly added in four portions and the mixture was stirred at room temperature for 10 minutes. (S)—(R)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.4 mmol) was dissolved in THF (0.4 mL) and added to the mixture. The resulting solution was placed in a microwave reactor for 30 minutes at 100° C., then cooled to room temperature. Hexanes (3×10 mL) was added, followed by water (10 mL). The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to yield the title compound as a clear oil (315 mg).
Reaction SMILES: CN(C)C=O.[CH2:6]([N:8]([CH2:23][CH3:24])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([NH2:22])=[N:13]1)[CH3:7].Br.Br[CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:23]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[C:16]([Cl:21])[CH:17]=[CH:18][CH:19]=2)[C:14]([NH:22][CH2:27][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[N:13]1)[CH3:24]
Reactant: CCN(CC)CCCBr
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.2 g of 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole prepared by the same method as described in Example 1, 9.0 g of 3-bromopropyldiethylamine hydrobromide and 7.9 g of anhydrous potassium carbonate. The mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the developing solvent to give 6.81 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4-chloroindazole having the following analytical values in a yield of 53%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH3:22])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Agent: [H-]
Agent: [Na+]
Product: CNc1ncnc2ccc(-c3cccc(F)c3)nc12

Procedure:
Following the same reaction and purification procedure, the amine 1 (150 mg, 0.62 mmol) was treated with sodium hydride 60% dispersion in mineral oil (37 mg, 0.94 mmol) and iodomethane (0.04 mL, 0.62 mmol) to provide 6-(3-fluorophenyl)-N-methylpyrido[3,2-d]pyrimidin-4-amine 26. LC/MS (ESI+): m/z 255 (M+H). 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.38-8.19 (m, 1H), 8.19-8.03 (m, 3H), 7.96 (d, J=8.5 Hz, 1H), 7.58 (dd, J=14.3, 7.8 Hz, 1H), 7.32 (dd, J=10.1, 8.0 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[CH:24]=[C:23]([C:35]([F:36])([F:37])[F:38])[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4Cl)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.9 %

Procedure:
To a cooled and stirred solution of 3′-[4-(2,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.36 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.25 g, 48%). MS (ISP) 524.2 [(M+H)+]; mp 202° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[CH:13][N:14]1CCCC1.O.NN>O1CCCC1.CO.[Ni].O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: O=[N+]([O-])c1cc(F)cc(Br)c1C=CN1CCCC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cc(Br)c2cc[nH]c2c1
Reaction time: 24 h
Yield: 43 %

Procedure:
To a solution of crude 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]-pyrrolidine (2.74 g) in tetrahydrofuran (25 ml) and methanol (25 ml) was added Raney nickel, 50% slurry in water, active catalyst (5.0 ml) followed by careful addition of hydrazine monohydrate (0.63 ml). After stirring for 24 hours the reaction mixture was filtered through celite and the filtrate reduced in vacuo. The residue was purified by flash chromatography to give 4-bromo-6-fluoro-1H-indole (0.80 g).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:28]([C:29](O)([CH3:31])[CH3:30])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(S(F)(F)[F:40])CC)C.C(#N)C.O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:28]([C:29]([F:40])([CH3:30])[CH3:31])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:33])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(O)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(F)c1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: -78 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-(2-hydroxypropan-2-yl)benzamide (0.067 g, 0.14 mmol) in anhydrous dichloromethane (10 mL) was added diethylaminosulfur trifluoride (22 μL, 0.17 mmol) at −78° C. The reaction mixture was stirred for 2 hours at −78° C. and then quenched by addition of saturated sodium bicarbonate solution (5 mL). The mixture was allowed to warm to ambient temperature and diluted with dichloromethane (50 mL). The organic phase was washed with brine (5 mL), dried over anhydrous magnesium sulfate, and filtered. The residue obtained after concentration of the filtrate in vacuo was purified by silica gel column chromatography using 0-20% ethyl acetate in hexanes as eluent to afford a beige solid. Lyophilization from acetonitrile and water (2 mL, 1:1) gave the title compound as colorless solid (0.012 g, 18%): 1H NMR (300 MHz, DMSO-d6) 11.74 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.11 (d, J=12.7 Hz, 1H), 4.05 (t, J=7.6 Hz, 4H), 3.69 (s, 2H), 2.23-2.11 (m, 2H), 2.04-1.97 (m, 3H), 1.79-1.61 (m, 18H); 19F NMR (282 MHz, CDCl3) 6-109.8 (s, 1F), −130.0 (s, 1F); MS (ES−) m/z 481.2 (M−1).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.N1C=CC=CC=1.[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1
Reactant: BrBr
Reactant: C1=Cn2cnnc2Cc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Brc1nnc2n1C=Cc1ccccc1C2

Procedure:
To 1.83 g of 11H-s-triazolo[3,4-b][3]benzazepine in 40 ml of chloroform was added 0.1 ml of pyridine and 0.55 ml of bromine was added dropwise under stirring. The mixture was stirred for 2 hours, after which it was washed with water and dried over Na2SO4. After evaporation of the solvent, the residue was treated with ether. By the above procedure was obtained 3-bromo-11H-s-triazolo[3,4-b][3]benzazepine as crystals. These crystals were recrystallized from ethanol and methanol in the order mentioned to obtain pale-brown platelets melting at 169°-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=O)[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=[N:33][NH:32][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NN=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3)c1cccnc1

Procedure:
Next, 0.33 g of 5,6,7,8-tetrahydro-2-(3-nitrophenyl)-3-formylimidazo[2,1-b]benzothiazol, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, water was added and the desired substance was obtained in an amount of 0.21 g (yield of 46.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:26]([C:31]3[CH2:32][CH2:33][O:34][CH2:35][CH:36]=3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:26]([CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:27][CH:28]=[CH:29][CH:30]=2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5C5=CCOCC5)ccc(F)c43)ccc21
Agent: [Pd]
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5C5CCOCC5)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of {(S)-6-[(R)-7-fluoro-4-(2-(3,6-dihydro-pyran-4-yl)-pyridin-3-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid (30 mg), 10% palladium on carbon (10 mg) and methanol (3 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 12 h. The mixture is filtered over Celite and the filtrate is concentrated to give the title compound. LC (method 9): tR=0.96 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:16][C:10]1[N:9]=[C:8]([CH:11]2[CH2:12][C:13](=[O:15])[CH2:14]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(c2nc(Br)c3c(Cl)nccn23)C1
Temperature: -4 °C
Reaction time: 0.08 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (47.7 g, 215 mmol) was dissolved in DMF (200 mL) under an atmosphere of nitrogen and cooled to −4° C. N-Bromosuccinimide (40.3 g, 226 mmol) was dissolved in DMF (140 mL) and slowly added to the reaction mixture. After 5 min, water (400 mL) was added and the resulting solid isolated by filtration and washed with solid with water to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 3.45-3.53 (m, 2H), 3.58-3.67 (m, 2H), 4.08-4.16 (m, 1H), 7.45 (d, 1H, J=5.2 Hz) and 8.30 (d, 1H, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([NH2:13])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:13]
Reactant: NC(=O)CCc1ccc(F)cc1F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: N#CCCc1ccc(F)cc1F
Temperature: 200 °C

Procedure:
74.0 g (0.40 mol) of 3-(2,4-difluorophenyl)propanamide are mixed with 124 g (0.87 mol) of phosphorus pentoxide, and the mixture is heated to 200° C. in an oil bath in a flask fitted with falling condenser. The resultant liquid is distilled off by applying a vacuum of about 67 mbar. 48.5 g of a colourless oil, which is subjected to fractional distillation at 120°-124° C. in vacuo (19 mbar), are obtained. 46.5 g (70% of theory) of the expected product are obtained.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].[OH-].[K+].[I-].[K+].Cl>CS(C)=O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([O:17][C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:16][CH2:15]3)=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
The 2-phenylchroman-6-ol (500 mg) and 1-chloro-4-methoxy-2-nitrobenzene (390 mg) were dissolved in DMSO (10 ml). Potassium hydroxide (230 mg) and potassium iodide (520 mg) were added and the resulting mixture was stirred at 90° C. for 1 hour. After cooling it was poured in to 1 M HCl-solution (20 ml) and extracted with dichloromethane. The combined organic layers were washed with water until neutral and then with saturated NaCl-solution and dried with Na2SO4. After evaporating the solvents the 6-(4-Methoxy-2-nitrophenoxy)-2-phenylchroman was obtained by trituration with methanol. 1H NMR (400 MHz, d6-DMSO) δ: 7.58 (d, 1H, J 3.1 Hz), 7.45-7.33 (m, 6H), 7.28 (dd, 1H, J 9.2 Hz, 3.1 Hz), 7.10 (d, 1H, J 9.2 Hz), 6.86-6.78 (m, 3H), 5.10 (dd, 1H, J 10.0, 1.9 Hz), 3.83 (s, 3H), 2.92 (ddd, 1H, J −16.9, 11.2, 5.9 Hz), 2.75 (ddd, 1H, J −16.9, 7.9, 4.2 Hz), 2.15 (m, 1H), 1.97 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][C@H:21]1[CH2:26][C@@H:25]([CH3:27])[CH2:24][NH:23][CH2:22]1.[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([N:23]2[CH2:24][C@H:25]([CH3:27])[CH2:26][C@H:21]([CH3:20])[CH2:22]2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2C[C@H](C)C[C@H](C)C2)ncn1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 96.2 %

Procedure:
Into 3 ml of N,N-dimethylformamide was resolved 0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.57 g of potassium carbonate and 0.25 g of cis-3,5-dimethylpiperidine hydrochloride was added therein, and the mixture was stirred for 40 minutes at 70° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-buthyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.41 g of 4-(2-butynyloxy)-6-(cis-3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (23)).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18]>>[OH:15][C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(O)CN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxy-2-methylpropylamine to provide 4-(2-hydroxy-2-methylpropylamino)3-nitroquinoline, m.p. 234°-244° C. (dec.).
Reaction SMILES: [Cl-].[CH2:2]([O:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:35][C:36]1([CH3:54])[CH:45]([N:46]2[C:50]([CH:51]=O)=[CH:49][N:48]=[CH:47]2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38](=[O:53])[O:37]1>C1COCC1>[CH2:2]([O:4][CH:5]=[CH:51][C:50]1[N:46]([CH:45]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](=[O:53])[O:37][C:36]2([CH3:54])[CH3:35])[CH:47]=[N:48][CH:49]=1)[CH3:3]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Reaction time: 0.25 h

Procedure:
To a solution of ethoxymethyltriphenylphosphonium chloride (0.426 g, 1.2 mmol) in THF (5 mL) at ambient temperature is added lithium hexamethyldisilazide (1M in THF, 1.3 mL, 1.3 mmol) and the mixture is stirred for 15 min. 3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.27 g, 1.0 mmol) (Example 9a) in THF (5 mL) and the mixture is stirred at ambient temperature overnight, then filtered. The filtrate is concentrated in vacuo to give crude 4-[5-(2-ethoxy-vinyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one, which is redissolved in methanol (5 mL). Pd/C (0.500 g) is added and the reaction vessel is flushed with hydrogen gas and stirred under balloon pressure at 50° C. overnight. The mixture is filtered, and the filtrate is concentrated in vacuo to give a residue which is purified by semi-preparative reverse phase HPLC to give 4-[5-(2-ethoxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 315.0 (M+H); 1H NMR (400 MHz, MeOD) of the HCl salt δ ppm 1.25 (t, J=6.9 Hz, 3 H), 1.32 (s, 3 H), 1.62 (s, 3 H), 3.29-3.37 (m, 2 H), 3.60-3.69 (m, 2 H), 3.79-3.97 (m, 2 H), 6.09 (s, 1 H), 7.57 (s, 1 H), 7.64 (d, J=7.6 Hz, 1 H), 7.73-7.79 (m, 1 H), 7.81-7.88 (m, 1 H), 8.32 (dd, J=7.7, 1.4 Hz, 1 H), 8.63 (br. s, 1H)