Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[F:19][C:20]1[CH:21]=[C:22]([CH3:30])[CH:23]=[C:24]2[C:29]=1[NH:28][CH2:27][CH2:26][CH2:25]2.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:28]1[C:29]2[C:24](=[CH:23][C:22]([CH3:30])=[CH:21][C:20]=2[F:19])[CH2:25][CH2:26][CH2:27]1)=[O:9]
Reactant: O=C(O)c1ccccc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1cc(F)c2c(c1)CCCN2
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)c2c(c1)CCCN2C(=O)c1ccccc1Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-benzoic acid (51.0 mg, 0.18 mmol, 1.0 equiv; Example 110, Step 1) in dichloromethane (2 mL) was added 8-fluoro-6-methyl-1,2,3,4-tetrahydro-quinoline (35.7 mg, 0.22 mmol, 1.2 equiv; [CAS RN 954260-80-1]), triethylamine (36.5 mg, 50 μL, 0.36 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (57.8 mg, 0.22 mmol, 1.2 equiv; [CAS RN 14338-32-0]). The reaction mixture was stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 20.7 mg (27%) of the title compound. MS (ISP): 430.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([O:26]C)=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.C1COCC1.[OH-].[Li+].Cl>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([OH:26])=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ccc2c(N(CCN3CCOCC3)S(C)(=O)=O)cccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O
Yield: 62.4 %

Procedure:
To a solution of methyl 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetate (1.08 g, 2.73 mmol) in a 1/1 mixture of THF and water (30 ml), lithium hydroxide (0.654 g, 27.3 mmol) was added, and the mixture reacted for 1 hour at room temperature. The mixture was acidified with aqueous 12 N HCl (pH=5) and the desired compound was extracted with EtOAc (3×50 ml). The organic phase was dried over sodium sulfate and the solvent was removed; the residue was purified by flash chromatography (DCM/MeOH 9/1) recovering 2-(4-(N-(2-morpholinoethyl)-methylsulfonamido)-1H-indol-1-yl)acetic acid (650 mg, 1.704 mmol 62.4% yield, MS/ESI+ 381.9 [MH]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1ncc(C#CCNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (2.81 g, 12.9 mmol) in TEA (25 mL) was added tert-butyl prop-2-yn-1-ylcarbamate (2.58 g, 16.6 mmol). The solution was degassed with argon. To the reaction mixture were added bis(triphenylphosphine)palladium(II) chloride (0.18 g, 0.26 mmol) and copper(I) iodide (0.098 g, 0.52 mmol). The reaction mixture was allowed to stir at 70° C. for 2.5 h and was then concentrated and diluted with EtOAc (100 mL). The mixture was filtered over a pad of Celite® and the resulting filtrate was washed with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl [3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-yl]carbamate (2.98 g, 79%) as a yellow solid. LCMS (FA): Rt=1.81 min, m/z=292.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[CH2:16]([C:23]1[O:27][C:26]([NH2:28])=[N:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:27][C:26]([NH:28][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)=[N:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: Nc1ncc(Cc2ccccc2)o1
Product: COc1cc(Nc2ncc(Cc3ccccc3)o2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 5-benzyl-oxazol-2-ylamine. The title compound was obtained as a yellow solid (Yield=22%). MS ISP (m/e): 361.3 (100) [(M+H)+].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([NH2:18])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O[CH:24](OCC)[N:25]([CH3:27])[CH3:26])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([N:18]=[CH:24][N:25]([CH3:27])[CH3:26])[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)Nc1ccc(CNc2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 0 °C

Procedure:
A mixture of 0.48 g (1.4 mmol) of 3-(4-acetylamino-benzylamino)-5-amino-4-cyano-pyrazole containing 21.06% THF, 0.245 ml (1.43 mmol) of N,N-dimethylformamide diethyl acetal and 4 ml of toluene is heated under reflux for 4.5 hours. The reaction mixture is then cooled to approx. 0° C. and filtered and the filter residue is washed with toluene, yielding the title compound; m.p. 206-211° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[O:4][CH:3]=1.[C:14]([NH:17][NH2:18])(=[O:16])[CH3:15]>>[C:14]([NH:17][NH:18][C:11]([C:8]1[CH:9]=[C:10]2[C:2]([Br:1])=[CH:3][O:4][C:5]2=[CH:6][N:7]=1)=[O:13])(=[O:16])[CH3:15]
Reactant: O=C(O)c1cc2c(Br)coc2cn1
Reactant: CC(=O)NN
Product: CC(=O)NNC(=O)c1cc2c(Br)coc2cn1
Yield: 95 %

Procedure:
In the same manner as in Reference Example 1 and using 3-bromofuro[2,3-c]pyridine-5-carboxylic acid instead of benzothiazole-6-carboxylic acid and acetohydrazide instead of tert-butyl carbazate, the title compound (yield 95%) was obtained as colorless amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[S:9](=[O:20])(=[O:19])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[OH:18])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:23])([F:24])[F:22])=[C:6]([C:8]2[S:9](=[O:19])(=[O:20])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[O:18][CH2:37][O:36][CH2:34][CH3:35])[CH:7]=1
Reactant: CCOCCl
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1cc(Cl)ccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCOC1=C(c2cc(Cl)ccc2C(F)(F)F)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C

Procedure:
To a mixture of 7-(5-chloro-2-trifluoromethyl-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C7 of Table C) (0.54 g) and N,N-diisopropylethylamine (0.25 ml) in N,N-dimethylformamide (5 ml) under nitrogen atmosphere was added chloromethyl ethyl ether (0.20 ml) and the reaction mixture was stirred at ambient temperature. After 2 hr further diisopropylethylamine (0.10 ml) and chloromethyl ethyl ether (0.10 ml) were added. After a further 3 hours stirring the reaction was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give 7-(5-chloro-2-trifluoromethyl-phenyl)-8-ethoxymethoxy-5H-6-thia-1,4-diaza-naphthalene 6,6-dioxide (0.276 g) 1H-NMR (400 MHz, CDCl3): 1.04 (3H, t), 3.25-3.41 (2H, m), 4.76-4.87 (2H, q), 5.13 (1H, d), 5.33 (1H, d), 7.58-7.61 (2H, m), 7.76 (1H, d), 8.62 (1H, d), 8.73 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](N)=[O:5].Cl.[OH-:14].[Na+]>>[NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:14])=[O:5]
Reactant: COc1ccc(C(N)=O)c(N)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(N)c1
Temperature: 25 °C

Procedure:
A solution of 27.4 g (0.165 mol) of 2-amino-4-methoxybenzamide in 500 mL of 1N sodium hydroxide was stirred and heated under reflux for 18 hours. After the reaction mixture had cooled to room temperature the solution was brought to pH 6-7 with 0.5N HCl. A white precipitate formed which was collected by vacuum filtration. The crystals were rinsed with water and dried overnight at 100° C. The product amounted to 23.9 g. An analytical sample (mp 176-178° C.) was obtained by recrystallization from ethyl acetate.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=1.[Li]CCCC.[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=O)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1.O>C1(C)C=CC=CC=1>[OH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N:49]1[C:58]2[C:53](=[CH:54][C:55]([CH:59]=[CH:60][CH:61]=[CH:17][C:14]3[CH:13]=[CH:12][C:11]([C:3]4[O:2][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=4)=[CH:16][CH:15]=3)=[CH:56][CH:57]=2)[CH2:52][CH2:51][CH2:50]1
Reactant: O=CC=Cc1ccc2c(c1)CCCN2CCCCCCO
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCN1CCCc2cc(C=CC=Cc3ccc(-c4nc5ccccc5o4)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 110 g (0.2 mole) of 4-(benzoxazol-2-yl)tolyltriphenylphosphonium bromide in toluene is added dropwise 0.2 mole of n-BuLi at room temperature. After 2 hours a solution of 28.7 g (0.1 mole) of 3-(N-hydroxyhexyl-1,2,3,4-tetrahydroquinolin-6-yl)acrolein in toluene is added dropwise to the mixture, and the reaction is stirred for 18 hours at room temperature. Water is added, and the solids are isolated by vacuum filtration, washed with 60% ethanol/water, and dried under vacuum. The product is purified by recrystallization from benzene.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:35](=[O:37])[CH3:36])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([C:28](=[O:30])[CH3:29])=[C:23]([OH:31])[C:22]=3[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:35]([C:9]1[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28](=[O:30])[CH3:29])=[C:23]([OH:31])[C:22]=2[CH2:32][CH2:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])[CH:15]=[CH:14]2)(=[O:37])[CH3:36]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1ccc2ccc(OCC(=O)OC)cc2c1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCOc1ccc2ccc(OCC(=O)O)cc2c1C(C)=O
Yield: 73.4 %

Procedure:
A mixture of 1.3 g of [[8-acetyl-7-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 48 ml of methanol and 24 ml of 1N sodium hyroxide was stirred at reflux for one hour and 20 minutes. The methanol was removed in vacuo the aqueous solution was acidified to pH 3. The sticky solid was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated in vacuo to give an oil which was crystallized from ether to yield 0.93 g (78%) of [[8-Acetyl-7-[3-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)propoxy]-2-naphthalenyl]oxy]acetic acid, mp 132°-134° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35]>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([NH2:36])=[O:35])=[N:5]2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1cccc(N)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(N)=O)c3)nn12
Yield: 14.9 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 3-Amino-benzamide (118 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 23.30 mg of 3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-benzamide as a lyophilized powder. (M+H)=360.11. 1H NMR (400 MHz, CDCl3) δ 9.39 (m, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.86 (d, 1H, J=7.64 Hz), 7.63 (d, 1H, J=8.00 Hz), 7.57 (d, 1H, J=7.80 Hz), 7.50 (t, 1H, J=7.56 Hz), 7.36 (t, 1H, J=7.88 Hz), 7.19 (d, 1H, J=5.00 Hz), 7.13 (m, 3H), 3.83 (s, 3H).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][O:17][C:11]3=[CH:10][C:9]=2[CH:8]=[CH:7]1)(C)(C)C.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[N:22]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[O:17]1[C:11]2=[CH:10][C:9]3[C:8]([C:25]4[CH:26]=[CH:21][N:22]=[C:23]([NH:27][CH:28]5[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]5)[N:24]=4)=[CH:7][NH:6][C:14]=3[CH:13]=[C:12]2[O:15][CH2:16]1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc3c(cc21)OCO3
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc5c(cc34)OCO5)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 5-(tert-butyl-dimethyl-silanyl)-5H-[1,3]dioxolo[4,5-f]indole (prepared by TBDMS protection of 5H-[1,3]Dioxolo[4,5-f]indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 555 mg (87%).
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][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.9 %

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 3-methylphenyl isocyanate (0.152 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, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 120 mg (38.8%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc2c(c1)OCCC2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-4-chromanone (2.0 g, 8.8 mmol) in dioxane (30 mL) was added 2-methylphenylboronic acid (1.8 g, 13.2 mmol), Pd(PPh3)4 (0.5 g, 0.44 mmol) and Na2CO3 (2.8 g, 26.4 mmol). The mixture was stirred at 100° C. under nitrogen overnight. The mixture was filtered and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to give 2.1 g (quantitative) of the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3): δ2.29 (s, 3H), 2.85 (t, J=6.3 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 6.94 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.19-7.32 (m, 4H), 7.93 (d, J=8.1 Hz, 1H). [M+H] Calc'd for C16H14O2, 239. Found, 239.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24](Cl)=[O:25])[CH2:2][CH2:3][CH3:4].[NH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24]([NH:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(C(=O)Cl)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Reactant: NN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (227 mg, 0.56 mmol) in CH2Cl2 (5 mL), were added 1-aminopiperidine (113 mg, 1.12 mmol) and Et3N (234 μL, 1.68 mmol). The solution was stirred overnight at rt, and then the solvents were evaporated under reduced pressure. The residue was purified by preparative reversed-phase HPLC, using 20 to 100% MeCN in water as gradient, to provide 125 mg (48%) of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.49-7.27 (m, 8 H), 2.93 (t, 2 H), 2.82 (bs, 4 H), 1.77-1.71 (m, 4 H), 1.46-1.37 (m, 4 H), 1.25-1.20 (2 H), 0.79 (t, 3 H). LC-MS m/z 471.33 (MH+), retention time 2.88 min (method 2).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:12][O:13][C:14](=[O:17])[CH2:15]Br.O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:17])[CH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)CBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1ccc2ccccc21
Reaction time: 24 h
Yield: 61.8 %

Procedure:
NaH (0.6 g, 15.0 mmol.) was added, while cooling with ice, to a solution of indole (1.17 g, 10.0 mmol.) and bromoacetic acid methyl ester (1.43 ml, 15 mmol.) in DMF. (20 ml), and stirring was carried out for 24 h at RT. For working up, water (50 ml) was added to the mixture, and extraction was carried out with EE (5×20 ml). The combined extracts were dried, filtered and concentrated. Chromatography with EE/cyclohexane (1:7) yielded 1.17 g of indol-1-yl-acetic acid methyl ester in the form of a colourless oil. These 1.17 g (6.18 mmol.) were dissolved in abs. methanol (100 ml); KOH (382 mg, 6.8 mmol.) was added and the mixture was heated at reflux for 2 h. For working up, the mixture was concentrated, water (20 ml) was added to the residue, the pH was adjusted to 4 with 1M HCl and the resulting solid was filtered off with suction. Indol-1-ylacetic acid was obtained in a yield of 0.96 g (white solid, m.p. 128–130° C.).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH2:14][NH2:15])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].[OH-].[Na+].O>CCOCC>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][NH:15][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(SCCN)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)NCCSc1ccc(OC(C)CC)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 2-[4-(1-methylpropoxy)phenylthio]-ethylamine (2.21 g, 8.65 mmol) in 25 ml of ether, at 0° and under N2, is added ethyl chloroformate (0.52 g, 4.76 mmol) by syringe, followed by addition of 10% aqueous sodium hydroxide (3.5 ml) and additional ethyl chloroformate (0.51 g, 4.76 mmol). After 15 min., the reaction is worked up by addition of water and extraction with ether. The combined organic phases are washed with 1N sulfuric acid, with water and with brine, dried and filtered, the filtrate is concentrated in vacuo and the product is purified by prep. TLC to give ethyl N-{2-[4-(1-methylpropoxy)-phenylthio]ethyl}carbamate (compound 76, Table A).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:30][CH2:29]2)=[CH:25][CH:24]=1
Reactant: COCCOc1ccc(OC2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: COCCOc1ccc(OC2CCN(CC(=O)N[C@@H]3COc4nc([N+](=O)[O-])cn4C3)CC2)cc1
Yield: 56.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-methoxyethoxy)phenoxy)piperidine (251 mg, 1.0 mmol) as crude materials, 134 mg title compound was generated and yield was 56%.
Reaction SMILES: Cl.O1CCOCC1.[N:8]([CH2:11][CH:12]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])(C)C)=[O:27])[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[N+:9]=[N-:10].C(=O)([O-])[O-].[K+].[K+].C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)OC[CH2:42][Si:43](C)([CH3:45])[CH3:44]>>[N:8]([CH2:11][CH:12]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH2:32][Si:43]([CH3:45])([CH3:44])[CH3:42])=[O:27])[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C(CN=[N+]=[N-])c2ccc(Br)cc2)CC1
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOC(=O)N1CCC(C(CN=[N+]=[N-])c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Preparation 1-B: A solution of hydrogen chloride in 1,4-dioxane (4 M, 60 mL, 240 mmol) was added to tert-butyl 4-[2-azido-1-(4-bromophenyl)ethyl]piperidinecarboxylate 13 (2.5 g, 6.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure. The residue containing 4-[2-azido-1-(4-bromophenyl)ethyl]piperidine hydrochloride 14 was dissolved in a 50% v/v aqueous tetrahydrofuran solution (68 mL). Potassium carbonate (2.12 g, 15.3 mmol) and 2-(trimethylsilyl)ethyl p-nitrophenyl carbonate (1.74 g, 61.4 mmol) were added. The reaction mixture was stirred at room temperature for 3 h. Organic solvent was evaporated under reduced pressure. Ethyl acetate was added. The organic layer was washed with aqueous sodium bicarbonate solution, water and brine. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography eluted with ethyl acetate-hexanes (1:5 v/v) to afford 2-(trimethylsilyl)ethyl 4-[2-azido-1-(4-bromophenyl)ethyl]piperidinecarboxylate 15 (2.1 g, 4.6 mmol). MS (LCMS-Electrospray) 454.1 MH+.