Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([NH:24]C(=O)OCC4C=CC=CC=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.CN1CCCC1=O.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH:18]=1)[O:16][C:11]1[N:10]=[C:9]2[S:8][C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:15][C:14]2=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN1CCCC1=O
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.7 %

Procedure:
To a solution of benzyl [3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]carbamate (14.4 g, 30.3 mmol) produced in Example 33(v) in ethanol (300 mL)/1-methylpyrrolidin-2-one (100 mL) were added 10% palladium carbon (27.3 g, 25.7 mmol) and ammonium formate (61.9 g, 909 mmol), and the mixture was stirred at room temperature for 5 days under a hydrogen atmosphere (1 atm). The insoluble material was filtered off through a celite pad, and the filtrate was concentrated under reduced pressure. To the obtained solution in 1-methylpyrrolidin-2-one was added water (300 ml), and the precipitated solid was collected by filtration and washed with water (500 mL). The solid collected by filtration was dissolved in a mixture of tetrahydrofuran (800 mL)/ethyl acetate (800 mL), washed with saturated brine (2×400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed successively with a mixture of tetrahydrofuran (10 mL)/diisopropyl ether (10 mL) and diisopropyl ether (40 mL) to give the title compound (7.29 g, 71%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([C:7](Cl)=[N:8]OS(C)(=O)=O)[CH2:4][O:3]1.[S-:16][C:17]#[N:18].[Na+].N1C=CC=CC=1.[CH3:26][C:27]1[C:32]([O:33][C:34]2[C:35]([NH2:47])=[N:36][CH:37]=[C:38]([S:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH:39]=2)=[CH:31][CH:30]=[CH:29][N:28]=1>O.C(OCC)(=O)C>[CH3:15][C:2]1([CH3:1])[O:6][C@H:5]([C:7]2[N:18]=[C:17]([NH:47][C:35]3[C:34]([O:33][C:32]4[C:27]([CH3:26])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:39][C:38]([S:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)=[CH:37][N:36]=3)[S:16][N:8]=2)[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](C(Cl)=NOS(C)(=O)=O)O1
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1N
Reactant: N#C[S-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2COC(C)(C)O2)ns1
Temperature: 40 °C
Yield: 77 %

Procedure:
A flask was charged with (S)-2,2-dimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (4.5 g, 18 mmol), sodium thiocyanate (1.3 g, 15 mmol), pyridine (3.8 ml, 46 mmol), and ethyl acetate (200 mL). The reaction was stirred and heated at 40° C. for 45 minutes. 3-(2-Methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (3.2 g, 10 mmol) was added and the reaction was stirred at 70° C. overnight. Water was added and the reaction was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (25 to 100% ethyl acetate in hexanes) to afford (R)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyri din-2-yl)-1,2,4-thiadiazol-5-amine (3.8 g, 7.7 mmol, 75% yield).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:24])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:18][N:14]1[C:15]2[C:11](=[C:10]([CH3:24])[C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[C:13]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cc2c(C)c(OCc3ccccc3)ccc2n1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(C)c(O)ccc2n1C
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A mixture of ethyl 5-benzyloxy-1,4-dimethyl-1H-indole-2-carboxylate (4.00 g, 12.4 mmol), ammonium formate (3.90 g, 61.8 mmol), 10% palladium/carbon (0.20 g) and ethanol (60 ml) was stirred at 60° C. for 1.5 hours. The catalyst was filtered off and the resulting filtrate was concentrated under reduced pressure. A 5% aqueous sodium chloride solution was added to the resulting residue, followed by extraction with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.89 g of ethyl 1,4-dimethyl-5-hydroxy-1H-indole-2-carboxylate.
Reaction SMILES: F[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:18])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:19])[C:6]=2[C:5](F)=[C:4]([F:21])[C:3]=1[F:22].[NH2:23][CH:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:25]>C(Cl)Cl>[CH2:30]([N:29]([CH2:32][CH3:33])[CH2:28][CH2:27][CH2:26][CH:24]([NH:23][C:5]1[C:6]2[C:7](=[O:19])[C:8]3[C:13](=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[OH:18])[C:14](=[O:16])[C:15]=2[C:2]([NH:23][CH:24]([CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:25])=[C:3]([F:22])[C:4]=1[F:21])[CH3:25])[CH3:31]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C1c2c(O)ccc(O)c2C(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: ClCCl
Product: CCN(CC)CCCC(C)Nc1c(F)c(F)c(NC(C)CCCN(CC)CC)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1,2,3,4-tetrafluoro-5,8-dihydroxyanthraquinone (0.47 g, 1.5 mmol) and 2-Amino-5-diethylaminopentane (2.3 mL) in CH2Cl2 (20 mL) was stirred at room temperature for 12 hours. After evaporation of the solvents, the residue was purified by silica gel chromatography using isocratic solvent system of CH2Cl2/MeOH/Et3N (100:10:1) yielding 364 mgs of Dye 2 as dark blue product. Abs (max, PBS pH 7.4)=667 nm; Em=700 nm. The structure of Dye 2 is given below:
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].Cl>CN1CCCC1=O>[NH:9]1[C:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)=[N:24][N:11]=[N:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Temperature: 150 °C

Procedure:
Triethylamine hydrochloride (41.25 g, 0.3 mol) and sodium azide (39 g, 0.6 mol) were added to a solution of 4-nitrophenylacetonitrile (32.4 g, 0.2 mmol) in anhydrous N-methylpyrrolidin-2-one (500 ml) and the mixture heated at 150° C. for 4h. The solution was cooled to room temperature and poured into 2N HCl (2 l) whereupon a solid crystallised out. The product was filtered, washed with water (500 ml) and hexane and dried in vacuo (37.4 g); δ (250 MHz, CDCl3) 4.34 (2H, s, CH2), 7.42 (2H, d, J=8.7 Hz, Ar--H), 8.12 (2H, d, J=8.7 Hz, Ar--H).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 65.9 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.11 mmol), 4-aminobutyric acid (3.76 g, 36.5 mmol) and NaOMe solution (54 mL, 27.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 35 mg of the title compound. MS: (+) m/z 483.16 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[CH:10]=2)[CH:6]=[C:5]([O:26][CH3:27])[C:4]=1[O:28][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[NH:57][C:56](=[O:58])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49]2)=[CH:44][C:43]=1[O:59][CH3:60]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(-c2cc(-c3cc(OC)c(OC)c(OC)c3)no2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 75.2 %

Procedure:
2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)phenol (29b) (387.38 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (34d) (546 mg, 80% yield).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH:17]([CH3:19])[CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH3:33])[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:26]([OH:37])=[CH:25]2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:17]([NH:16][C:5]1[C:4]([CH2:3][C:25]2[C:24]3[C:29](=[CH:30][C:31]([O:32][CH3:33])=[C:22]([O:21][CH3:20])[CH:23]=3)[C:28]([CH2:34][CH2:35][CH3:36])=[N:27][C:26]=2[OH:37])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)([CH3:19])[CH3:18]
Reactant: COc1ccc2nc(NC(C)C)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-(chloromethyl)-N-isopropyl-6-methoxyquinolin-2-amine hydrochloride SLA 28190 (305 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (250 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 94:6) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided 61 mg of 4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(isopropylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 53 as a yellow solid (68 mg, 12% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[S:21][C:20]([C:22]#[N:23])=[CH:19][C:18]=1[CH3:24]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[S:21][C:20]([C:22]#[N:23])=[CH:19][C:18]=3[CH3:24])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OCC(=O)N2

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile using the coupling procedures in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.87 (s, 1H), 7.41-7.36 (m, 2H), 7.22 (d, J=8.32 Hz, 1H), 4.29 (s, 2H), 2.29 (s, 3H), 1.58 (s, 6H); MS (FI) m/z 311 ([M−H]−, 20%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[OH:28].N1CCCCC1.[BH4-].[Na+]>C(O)C.CO>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]#[N:16])=[C:2]([NH:1][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH:18]([F:17])[F:29])=[C:21]([OH:28])[CH:22]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(OC(F)F)c(O)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-(difluoromethoxy)-3-hydroxybenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product was scraped and collected. (100 mg)
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[F:27].[Li+].[OH-]>>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[F:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1F)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1F)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid as colorless liquid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13]N1C(=O)CCC1=O.[C:21]([O:28][CH3:29])(=[O:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24]>C(OC(=O)C)C.CCCCCC>[CH3:26][O:25][C:23](=[O:24])[CH:22]([Br:13])[C:21]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(Br)C(=O)OC

Procedure:
p-Toluene sulfonic acid monohydrate (11.0 g, 0.057 mol) and N-bromosuccinimide (1.74 g, 0.009 mol) were slowly added to a stirred solution of dimethyl malonate (5.0 g, 0.037 mol) in CH3CH (30 mL). The resulting mixture was heated at reflux for 2 hours, evaporated and dissolved in dichloromethane. The organic layer was washed with H2O, dried over MgSO4 and concentrated. An analytically pure sample was to obtained by column chromatography on silica gel using a 1:4 mixture of ethylacetate/hexane. Yield: 6.0 g (76.0%).
Reaction SMILES: [C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31](F)=[O:32])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[NH3:34]>>[C:1]([O:11][C:12]([C:18]([O:21][C:22]([C:31]([NH2:34])=[O:32])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])([F:20])[F:19])([C:14]([F:17])([F:16])[F:15])[F:13])([C:4]([C:7]([F:10])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=C(F)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reactant: N
Product: NC(=O)C(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F
Reaction time: 3 h
Yield: 85.5 %

Procedure:
The acid fluoride, C3F7OCF(CF3)CF2OC(CF3)2COF, (4.51 g, 8.20 mmol) was reacted with ammonia (18.88 mmol) in vacuo at -78° C. for 10 minutes, then at -23° C. for 3 hours. The volatiles were removed at room temperature by pumping and the involatile residue was treated with dry Freon 113 (20 ml) and filtered in an inert atmosphere enclosure. The filtrate, after Freon 113 removal, gave 3.82 g (86% yeild) of C3F7OCF(CF3)CF2OC(CF3)2CONH2 which was characterized by mass spectrometry. MS(70 eV) m/e (intensity, ion): 526 (2.1%, M-F), 360 (29.4%, M-C3F7O), 260 (7.0%, CF2OC(CF3)2CONH2), 194 (17.2%, C(CF3), 169 (25.7%, C3F7), 69 (48.4%, CF3), 44 (100%, CONH2), 169 (25.7%, C3F7), 69 (48.4%, CF3), 44 (100%, CONH2).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(C)cc3)CC2)ccc1Cl
Yield: 56 %

Procedure:
The title compound (22 mg, 56%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 4-methylbenzoyl chloride. MS: 387.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl>>[ClH:1].[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Agent: Cl
Product: O=Cc1c(N2CCNCC2)n(-c2ccc(F)cc2)c2ccccc12
Yield: 40 %

Procedure:
2-Chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-fluorophenyl)-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde hydrochloride (40% yield) as a cream solid. ESI/MS 324 (M+H); RT=2.44 min; NMR 10.15 (1H, s); 8.13 (1H, d, J=9 Hz); 7.71 (2H, m); 7.54 (2H, m); 7.23 (2H, m); 6.95 (1H, d, J=9 Hz); 3.33 (4H, br s); 2.95 (4H, br s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:28]([Cu])#[N:29]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[C:9]2=[C:10]([C:28]#[N:29])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 508 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][S:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([S:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC(C)(C)CCSc1cccc(B(O)O)c1
Product: CC(C)(C)CCSc1cccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)c1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, J and C stepwise) (112 mg, 0.2 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butylsulfanyl)phenylboronic acid (96 mg, 0.4 mmol, prepared according to general procedure I) to give 5-(3-{4-(2,4-difluoro-phenyl)-2-[3′-(3,3-dimethyl-butylsulfanyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC=C([F:62])C=1)#C>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:62])[CH:26]=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Reactant: C#Cc1cccc(F)c1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3-fluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1N.C(#[N:26])C>>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:14]([NH2:26])=[O:15]
Reactant: CC#N
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1ccccc1F
Product: COc1ccc(C(F)(F)F)cc1N(C(N)=O)c1ccccc1F
Temperature: 82 °C

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (1057.8 g) is dissolved in acetonitrile (4240 ml), then 2-fluoroaniline (540.8 g) is added thereto and the mixture is rinsed in with acetonitrile (50 ml). The resulting clear solution is stirred under reflux (ca. 82° C.) for 4 h, then seeded at ca. 78° C. and stirred for ca. 15 min. The suspension is cooled to 0° C., and the product is filtered off with suction and washed with acetonitrile (950 ml, cooled to 0-5° C.). The product is dried overnight at 45° C. in a vacuum drying oven using entraining nitrogen. A total of 1380.8 g of N-(2-fluorophenyl)-N-[2-methoxy-5-(trifluoromethyl)phenyl]urea are obtained as a solid, corresponding to 86.4% of theory.