Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:40])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)(Cl)Cl>[CH3:40][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][C:20]([NH:22][C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCc1nc2cc(N)ccc2n1CCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCc1nc2cc(NC(=O)c3ccccc3)ccc2n1CCCN(C)C
Temperature: 25 °C

Procedure:
Triethylamine is added to a solution containing Compound 27 in chloroform, and then benzoyl chloride is added thereto while being cooled with ice. The mixture is stirred at room temperature to give the entitled compound.
Reaction SMILES: I.[NH2:2][CH:3]([S:10][CH3:11])/[N:4]=[C:5](/N(C)C)\[CH3:6].Cl[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:6][C:5]1[N:4]=[C:3]([S:10][CH3:11])[NH:2][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CSC(N)/N=C(\C)N(C)C
Reactant: CCOC(=O)CC(=O)Cl
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (73.0 g, 0.26 mole) in dry dichloromethane (900 mL), was added ethyl 3-chloro-3-oxopropanoate (44 mL, 95% Lancaster, 0.34 mole) was added under a nitrogen atmosphere. The mixture was stirred for 4 h at room temperature, cooled to 0° C. then triethylamine (107 mL, 0.78 mole) was added. The reaction mixture was stirred overnight. The solvent was removed and H2O was added. The pH was adjusted to pH=5.0 with acetic acid and extracted with ethylacetate then evaporated and crystallized from the appropriate solvent (Ethylacetate-Hexanes mixture solvent, approximately 20% ethylacetate-Hexanes). This afforded ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (36.5 g, 62% yield) after drying under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:41]1.BrCCCC.O1C2(CCNCC2)OCC1>O>[CH2:46]([N:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:13]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([C:8]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:30][CH2:31]4)=[O:24])=[CH:21][CH:22]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])=[O:15])[CH2:41][CH2:42]1)[CH2:47][CH2:48][CH3:49]
Reactant: CCCCN1CCC(N)CC1
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Agent: C1CC2(CCN1)OCCO2
Solvent: CCCCBr
Solvent: O
Product: CCCCN1CCC(NC(=O)c2cnc3c(OC)cccc3c2Nc2ccc(C(=O)NC3CCN(Cc4ccccc4)CC3)cc2)CC1

Procedure:
N-(1-Butyl-4-piperidinyl)-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared as a hygroscopic material (0.215 hydrate) by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and 4-amino-1-butylpiperidine as described for Example 17, Step 5. 4-Amino -1-butyl-piperidine can be prepared from 4-bromobutane and 1,4-dioxa-8-azaspiro[4.5]-decane as described in U.S. Pat. Nos. 3,875,165 and 4,816,464: mp 215°-220 ° C.; 1H NMR (Me2SO-d6, 400 MHz) δ 9.50 (s, 1 H), 8.77 (s, 1 H), 8.39 (d, J=7.5 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H), 7.70 (d, J=8.6 Hz, 2 H), 7.57 (d, J= 8.4 Hz, 1 H), 7.41 (m, 1 H), 7.18-7.32 (m, 6 H), 6.88 (d, J=8.6 Hz, 2 H), 3.95 (s, 3 H), 3.72-3.76 (m, 1 H), 3.44-3.49 (m, 3 H), 2.68-2.80 (m, 4 H), 2.14-2.19 (m, 2 H), 1.95-2.01 (m, 2 H), 1.71-1.83 (m, 4 H), 1.53-1.60 (m, 4 H), 1,1-1.4 (m, 6 H), 0.8 (t, J=7.24 Hz, 3 H); Karl Fischer, 0.58% H2O.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][NH:30][CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][N:30]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1
Reactant: Nc1nc2cc(Br)ccc2c2c1nc1n2CCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(Br)ccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Triethylamine (3.82 g, 37.7 mmol) and methanesulfonyl chloride (2.38 g, 20.7 mmol) were sequentially added to a solution of 3-bromo-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (6.00 g, 18.9 mmol) in DMF (50 mL), and the mixture was stirred at ambient temperature overnight. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried to provide 600 mg of 3-bromo-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 315-317° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].F[C:7]1[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])=[N:9][CH:10]=[CH:11][C:12]=1[I:13]>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH:14]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])[CH3:15])[C:7]=1[O:1][CH2:2][CH3:3]
Reactant: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOc1c(I)ccnc1C(C)n1c(C)ccc1C
Yield: 8.5 %

Procedure:
A solution of sodium ethoxide was initially prepared by dissolving 2.0 g (87 mmole) of sodium metal in 300 ml of anhydrous absolute ethanol. To the stirring solution thus prepared was added 3.5 g (10.2 mmole) of N-[(3-Fluoro-4-iodopyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole and the mixture was refluxed under nitrogen for 4 days. The solution was cooled, diluted to 1 liter with water, and extracted with ethyl acetate (2×). The organic layer was dried over sodium sulfate, filtered, and concentrated to a resin. Chromatography over flash silica gel (30% ethyl acetate in hexanes) gave initially 320 mg (8.5%) of N-[(4-Iodo-3-ethoxypyrid-2-yl)-eth-2-yl]-2,5-dimethylpyrrole: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d, 1H), 7.62 (d, 1H), 5.80 (s, 2H), 4.10 (t, 2H), 4.00 (q, 2H), 3.15 (t, 2H), 2.20 (s, 6H), 1.45 (t, 3H); MS (FD) m/e 370 (Mt). Further elution provided the titled compound, 1.7 g (64%): IR (KBr, cm-1) 2991, 1608, 1495, 1309, 1075; 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, 1H), 7.15 (t, 1H), 5.60 (s, 2H), 4.20 (q, 2H), 4.10 (t, 2H), 2.98 (dt, 2H), 2.10 (s, 6H), 1.38 (t, 3H): MS (FD) m/e 262 (Mt). Anal. Calc'd. for C15H19FN2O 0.25 H2 O: C, 67.55; H, 7.31; N, 10.50. Found: C, 67.56; H, 7.35; N, 10.46.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1)[CH3:4].[CH2:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CO>[CH2:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=2)[C:11]#[N:12])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: CCOc1ccc(CC#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCOc1ccc(C=C(C#N)c2ccc(OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g of KOH were dissolved in 30 ml of methanol whilst being heated. The solution was cooled down to room temperature, after which 3.3 g of p-ethoxybenzylcyanide and 4 g of p-hexyloxybenzaldehyde were added. The mixture was stirred and subsequently stored at room temperature for 1 hour and then at -25° C for 2 hours. The crystallisate was filtered off and subsequently recrystallized from methanol and petroleum ether (60-80). Melting point 53.5°-54° C. Transition point nematic-isotropic 80° C. In a similar way the following compounds were obtained:
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:15]C[CH:13](O)[CH2:12]1.C(OC(C)C)(C)C.O1CCOCC1>>[C:1]([O:9][CH:10]1[CH2:13][CH2:12][NH:11][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: OC1CCNC1
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: O=C(OC1CCNC1)c1ccccc1
Yield: 66 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), pyrrolidin-3-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether/1,4-dioxane (3/1) (5.0 ml) was heated to reflux for 46 hours, and as a result, pyrrolidin-3-yl benzoate was obtained at a yield of 66%. The yield of N-benzoylpyrrolidin-3-yl benzoate was 34%.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[O:9]=[C:10]1[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:23]2[N:22]=[CH:21][N:14]3[CH2:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:12]([C:13]=23)=[CH:11]1>CN(C=O)C>[CH3:1][CH:15]1[N:14]2[CH:21]=[N:22][C:23]3[CH:24]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:9])[CH:11]=[C:12]([C:13]=32)[NH:19][CH2:18][CH2:17][C:16]1=[O:20]
Reactant: CC(C)(C)OC(=O)CC1C(=O)C=C2NCCC(=O)Cn3cnc1c32
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1C(=O)CCNC2=CC(=O)C(CC(=O)OC(C)(C)C)c3ncn1c32
Reaction time: 18 h

Procedure:
Cesium carbonate (214 mg, 0.66 mmol) and iodomethane (93 mg, 0.66 mmol) were added to a solution of tert-butyl (2,7-dioxo-5,6,7,8-tetrahydro-4H-imidazo[1,5,4-fg][1,6]benzodiazocin-1(2H)-yl)acetate (109 mg, 0.33 mmol, described in Intermediate 13) in DMF (5 mL). After 18 h, the mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=346 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[F:29])[CH2:41][CH2:40]1)=[O:16]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 72.3 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (532 mg, 1.33 mmol, 72%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH2:27][CH2:28][CH2:29]S(C1C=CC=CC=1)(=O)=O)=[CH:24][CH:23]=[CH:22][CH:21]=2.C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:29][CH2:28][CH2:27][C:26]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][C:18]=4[CH3:17])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Yield: 31 %

Procedure:
A stirred mixture, under nitrogen, of 27.0 g of 3-(4-piperidyl-6-chloro-1,2-benzisoxazole, 31.3 g of 2-methyl-3-(3-phenylsulfonylpropyl)indole and 27.6 g of anhydrous potassium carbonate in 500 ml of methyl ethyl ketone was heated under reflux for 6 hrs. The mixture was cooled and treated with 150 ml of water. The organic phase was separated, extracted with water and concentrated to an oily residue. The residue was dissolved in 50 ml of ethyl acetate and absorbed on a chromatography column containing 300 g of silica gel packed in ethyl acetate. Elution with ethyl acetate, followed by concentration of the eluent and trituration with ether, provided 12.1 g (31% yield) of product. Recrystallization from a small volume of toluene afforded the anlytical sample, mp 108°-110°.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH2:20])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O.O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[N:10]([CH3:21])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
To 2-{[5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 5) (250 mg) in dimethyl acetamide (2 ml) at room temperature was added sodium hydride (41 mg, 60% dispersion in oil), the mixture was stirred for 5 minutes. To the mixture was added 4-tert-butylbenzenesulphonyl chloride (79 mg), the mixture was stirred for a further 1 hour. The reaction was diluted with water (20 ml) and extracted with diethyl ether (20 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with dichloromethane:ether (1:1) to yield the title compound as a pale orange solid (40 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.CO.[CH3:16][NH2:17]>O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([NH:17][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: CO
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1
Reaction time: 1.5 h

Procedure:
In a stirred mixture consisting of 202.6 g (1 mole) of 2-chlor-6-ethoxy-3-nitropyridine and 500 ml of methanol, 202 g (2.6 mole) of a 40% monomethylamine solution is added drop by drop while stirring in the course of 90 minutes and at 25°-30° C. sump temperature. Subsequently, the mixture is again stirred for yet another 5 hours, is reacted with 650 ml of water, and then the product is filtered off by suction, is washed again with ample water and dried. Melting point 106°-7° C., Yield: 183.2 g (92.9% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:21][C:20]([OH:22])([CH2:19][CH2:18][NH:17][C:2]1[N:3]=[N:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)[CH3:23]
Reactant: CC(C)(O)CCN
Reactant: Clc1ccc(C#Cc2ccccc2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(O)CCNc1ccc(C#Cc2ccccc2)nn1
Yield: 26.9 %

Procedure:
A solution of 3-chloro-6-(phenylethynyl)pyridazine (CAS 77778-15-5) (125 mg, 0.582 mmol) and 4-amino-2-methylbutan-2-ol hydrochloride (244 mg, 1.75 mmol, 3 equiv.) and triethylamine (206 mg, 284 ml, 2.04 mmol, 2 equiv.) in 1.25 ml of pyridine was heated 20 hours at 85° C. The solvent was removed in vaccuo. The residue was taken up in ethyl acetate/methanol, adsorbed onto 4 g of silica and purified on a 20 g flash chromatography column using a heptane/ethyl acetate 85:15 to 15:85 gradient to yield 44 mg (27% yield) of the title compound as a crystalline white solid, MS: m/e=282.2 (M+H+).
Reaction SMILES: COCCOC[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CCOC(C)=O.[Zn+2].[Br-].[Br-]>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:7])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of (2′-methoxyethoxymethoxy-[1,1′;3′1″]terphenyl-5′-yloxy)butane (0.237 g, 0.583 mmol) in CH2Cl2 (6 mL) at room temperature was added anhydrous ZnBr2 (0.656 g, 2.92 mmol). After 18 h at this temperature, the resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (10% EtOAc/petroleum ether) to afford the product (0.172 g, 92%) as a solid; 1H NMR (CDCl3) δ0.97 (t, J=10.9 Hz, 3H), 1.39-1.60 (m, 2H), 1.68-1.87 (m, 2H), 3.97 (t, J=9.5 Hz, 2H), 5.05 (s, 1H), 6.87 (s, 2H), 7.32-7.62 (m, 10H); mass spectrum [(+) ESI], m/z 319 (M+H)+, 341 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.[Pd]>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Reactant: C=Cc1ccccc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=C/c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)\c1ccccc1
Yield: 16 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (200 mg, 0.58 mmol), styrene (91 mg, 0.87 mmol), tri(o-tolyl)phosphine (14.2 mg, 0.047 mmol), triethylamine (295 mg, 2.91 mmol) and palladium actetate (5.23 mg, 0.023 mmol) in acetonitrile (5 ml) was heated under reflux conditions for 23 h, evaporated and purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) to yield the title compound as white solid (34 mg, 16%). MS (ISP): m/e=367.2 (M+H+); m.p. 162° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([O:24][CH3:25])[CH:13]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=O)=O>CN(C)C=O>[CH3:25][O:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:9]2[S:8][C:7]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=3)=[N:6][C:5]=2[CH2:4][CH2:3][CH2:2][S:44][CH3:43])[CH:17]=[CH:16][C:15]=1[C:18]1[NH:22][C:21](=[O:23])[O:20][N:19]=1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCO)ccc1-c1noc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCSC)ccc1-c1noc(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg of 3-{4-[4-(3-hydroxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 mL of dimethylformamide at 0° C. were added 0.077 mL of triethylamine and 0.015 mL of methanesulfonyl chloride. The resulting mixture was stirred at 0° C. for 30 minutes and then concentrated under reduced pressure. The product was dissolved in 3 mL of dimethylformamide. To the resulting solution were added 5.5 mg of sodium methanethiolate and 13 mg of potassium iodide. The reaction mixture was heated for 10 minutes to 90° C. under microwave irradiation in a sealed tube. It was then concentrated under reduced pressure, taken into dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 20 mg of 3-{2-methoxy-4-[4-(3-methylsulfanyl-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
A sample of crude 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (40.8 g, 0.14 mole) was dissolved in methylene chloride (300 mL). The solution was treated with oxalyl chloride (15.7 mL, 0.18 mole), followed by N,N-dimethylformamide (12 drops). Off-gassing began shortly after adding the N,N-dimethylformamide catalyst. The reaction mixture was stirred for about 20 minutes under ambient conditions, then was heated to reflux for a period of 35 minutes. Volatiles were removed by concentrating the reaction mixture on a rotary evaporator at a bath temperature of 55° C. The crude product, approximately 43 g of a light-yellow oil, was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.1 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[2-(morpholin-4-yl)phenoxy]-phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.47 g of the desired compound were obtained.