Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[O:13].[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH:19]=[C:18]2[CH:33]=[C:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:13])[NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[CH:19]=[C:18]2[CH:33]=[C:34]1[S:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]
Reactant: Nc1ccc2c(c1)c(C=C1SC(=O)NC1=O)cn2Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(N=C=O)c(OC)c1
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)c(C=C2SC(=O)NC2=O)cn3Cc2ccc(Cl)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by General Procedure 7 with 2,4-dimethoxyphenyl isocyanate and the amino compound from Example 47 as reactants. Nmr and ms data were consistent; ms m/e 598 (M+1). HPLC (System 1): purity greater than 80%.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[C:22]1([CH2:28]C[Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (21.93 g, 97 mmol) in absol. THF (180 ml) was added dropwise to a 1 M solution of phenylethylmagnesium chloride in THF (242 ml, 242 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[N:45]2[CH:46]=[CH:47][N:48]=[C:44]2[CH:43]=[CH:42][CH:41]=1>C1COCC1.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.[Cu]I>[N:48]1[CH:47]=[CH:46][N:45]2[C:40]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:17]4[S:18][C:10]([CH2:9][N:6]5[CH2:5][CH2:4][CH:3]([N:2]([CH3:38])[CH3:1])[CH2:8][CH2:7]5)=[CH:11][C:12]=4[N:13]=3)=[CH:41][CH:42]=[CH:43][C:44]=12
Reactant: Brc1cccc2nccn12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)C1CCN(Cc2cc3nc(-c4cccc5nccn45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 62.8 %

Procedure:
A mixture of dimethyl-[1-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperidin-4-yl]amine (156 mg, 0.24 mmol), 5-bromoimidazo[1,2-a]pyridine (56 mg, 0.29 mmol), Pd(PPh3)4 (28 mg, 0.02 mmol) and copper(I) iodide (55 mg, 0.29 mmol) in THF (2.5 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (5 g), washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 10:90) to give 688 as a white solid (72 mg, 63%). LCMS (Method F): RT 3.89 min; [M+H]+ 478. 1H NMR (400 MHz, CHCl3-d): δ 9.23 (s, 1 H); 7.95 (dd, J=8.6, 1.3 Hz, 1 H); 7.77 (d, J=8.6 Hz, 1 H); 7.75 (d, J=1.3 Hz, 1 H); 7.35 (s, 1 H); 7.32-7.29 (m, 1 H); 4.07 (t, J=4.8 Hz, 4 H); 3.91 (t, J=4.8 Hz, 4 H); 3.84 (s, 2 H); 3.04 (d, J=11.25 Hz, 2 H); 2.33-2.25 (m, 6 H); 2.21-2.10 (m, 3 H); 1.84 (d, J=12.5 Hz, 2 H); 1.61 (m, 2 H)
Reaction SMILES: [Br:1][CH:2]1[CH2:8][CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([CH:35](I)[C:36]([NH2:38])=[O:37])(C)(C)C.Cl>O1CCCC1.CS(C)=O>[C:6]([NH:38][C:36](=[O:37])[CH2:35][N:4]1[C:5]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=2[CH:7]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH2:8][CH:2]([Br:1])[C:3]1=[O:20])([CH3:15])([CH3:7])[CH3:5]
Reactant: Cc1ccc2c(c1)NC(=O)C(Br)CC2C1CCCCC1
Reactant: CC(C)(C)C(I)C(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)N(CC(=O)NC(C)(C)C)C(=O)C(Br)CC2C1CCCCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a 125 mL round-bottomed flask equipped with nitrogen inlet were added 4.7 grams (13.97 mmol) 3-bromo-5-cyclohexyl-8-methyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one and 70 mL dry tetrahydrofuran. The solution was cooled to -78° C., and 16.8 mL (16.76 mmol) of a 1N solution of sodium bistrimethylsilylamide in tetrahydrofuran was added, followed by a solution of 4.04 grams (16.76 mmol) of t-butyl iodoacetamide in 35 mL dry tetrahydrofuran dropwise over 15 minutes. The reaction was stirred for 10 minutes, then warmed, 35 mL dry dimethylsulfoxide added, and the reaction stirred at room temperature for 14 hours. It was then poured into 1N hydrochloric acid, extracted into ethyl acetate, and the organic layer washed with water, saturated aqueous sodium bisulfite solution, brine, dried, and evaporated. The residue was chromatographed on silica gel with hexane/ethyl acetate to afford the two diastereomeric products, the less polar isomer, M.P. 183°-186° C., 2.16 g, 34% yield, and the more polar isomer, M.P. 206.5°-207.5° C., 3.16 g. 50% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.424 g. of pelargonic acid chloride as in Example 1. The 0.722 g. of yellow crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.617 g. of colorless crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl nonanoate obtained melts at 43.2°-43.6° and has a clearing point of 74.0°. The compound is smectic up to 61.3°. UV (EtOH): ε272 = 26,900.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:21]([CH2:20][CH2:19][CH2:18][Cl:17])(=[O:23])=[O:22])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: O=S(=O)(Cl)CCCCl
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)CCCCl)c2c1C
Yield: 70 %

Procedure:
4-(3-Chloro-propane-1-sulfonylamino)-3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and 3-chloropropanesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 70%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (m, 3 H) 2.2 (m, 2 H) 2.8 (s, 3 H) 3.3 (m, 2 H) 3.8 (t, J=6.4 Hz, 2 H) 4.4 (q, J=7.2 Hz, 2 H) 7.2 (d, J=7.3 Hz, 1 H) 7.5 (m, 1 H) 7.7 (m, 1 H) 9.7 (s, 1 H).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]#[CH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(BC(C(C)C)C)(C(C)C)C.[Br-:42]>>[Br:42]/[CH:11]=[CH:10]/[CH:9]([O:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CC(CCCCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Br-]
Agent: CC(C)C(C)BC(C)C(C)C
Product: CCCCCCCC(/C=C/Br)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Treatment of 3-triphenylmethoxy-1-decyne (Example 129) with disiamylborane and the bromide by the procedure described in Example 1173 is productive of the title compound.
Reaction SMILES: [C:1](OCCOC(=O)C(C)=C)(=O)[C:2](C)=[CH2:3].COC.[C:18]1([CH:25]=[CH:24][C:22](O)=[CH:21][CH:20]=1)O>>[CH:2]([C:18]1[CH:25]=[CH:24][CH:22]=[CH:21][CH:20]=1)([CH3:3])[CH3:1]
Reactant: C=C(C)C(=O)OCCOC(=O)C(=C)C
Reactant: Oc1ccc(O)cc1
Agent: COC
Product: CC(C)c1ccccc1

Procedure:
85.6 g ethylene glycol dimethacrylate (Aldrich, 98%, 100 ppm methyl ether of hydroquinone (MEHQ)
Reaction SMILES: [N:1](C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH2:35]O)[CH:33]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)NC(=O)C2=CC=CC=C12>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][NH2:1])[CH:33]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CO)cc32)CC1
Agent: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3ccc(CN)cc32)CC1
Yield: 105.4 %

Procedure:
Under ice cooling, a solution of diethyl azodicarboxylate (4.6 g) in tetrahydrofuran (20 ml) was added dropwise into a solution of 1-[1-(t-butoxycarbonyl)piperidin-4-yl]-6-hydroxymethylindoline (7.9 g), triphenylphosphine (6.9 g) and phthalimide (3.9 g) in tetrahydrofuran (250 ml) and the resultant mixture was stirred at room temperature for 3 hr. After concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system). Then hydrazine hydrate (3.6 g) and ethanol (150 ml) were added thereto followed by healing under reflux for 2 hr. After ice cooling, the resulting crystalline precipitates were filtered off and the filtrate was concentrated under reduced pressure to give the title compound (8.3 g).
Reaction SMILES: [ClH:1].[CH2:2]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])[CH:3]=[CH2:4].[H][H]>O1CCCC1.[Pd]>[ClH:1].[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][CH2:2][CH2:3][CH3:4])[CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: C=CCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CCCNS(=O)(=O)c1cc(C(=O)O)ccc1N1CCN(C)CC1

Procedure:
37.6 Grams of 3-allylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoic acid-hydrochloride (0.1 mole), prepared according to Example 32, were dissolved in 0.3 l of tetrahydrofurane and were hydrogentated in the presence of palladium black at 30° C. and at 40 atmospheres until no more hydrogen was absorbed. Subsequently the catalyst was separated, the solution was evaporated, and the residue was recrystallized from water.
Reaction SMILES: [NH3:1].[F:2][C:3]1[N:8]=[C:7]([C:9](=[NH:11])[O-])[C:6](=[O:12])[NH:5][CH:4]=1>C(O)C>[F:2][C:3]1[N:8]=[C:7]([C:9](=[NH:1])[NH2:11])[C:6](=[O:12])[NH:5][CH:4]=1
Reactant: N=C([O-])c1nc(F)c[nH]c1=O
Reactant: N
Solvent: CCO
Product: N=C(N)c1nc(F)c[nH]c1=O
Temperature: 0 °C
Reaction time: 17 h

Procedure:
At an ice-cooled temperature, gaseous ammonia was introduced into 2.0 mL of ethanol to prepare a saturated solution, and then 0.10 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidoate and 2.0 mL of ethanol were added. After elevating the temperature to room temperature, the mixture was left to stand for 17 hours. The deposited solid product was collected by filtration and washed with ethanol. The residue thus obtained was purified by silica gel column chromatography [eluent: chloroform:methanol=10:1], ethanol was added to the purified product, and the solid product was collected by filtration. Thus, 20 mg of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboximidamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:17]=1[CH2:18][NH:19][C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C(O)CO>C(O)(C)C.[Cu](I)I>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:22]2[CH2:23][CH2:24][CH:20]([NH:19][CH2:18][C:17]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:16]=3[Cl:15])[CH2:21]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(CN[C@H]2CCNC2)c(Cl)c1
Reactant: Clc1ccc(I)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Clc1ccc(CNC2CCN(c3ccc(Cl)nc3)C2)c(Cl)c1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Add 2-chloro-5-iodopyridine (193 mg, 0.84 mmol) to a mixture of potassium carbonate (344 mg, 1.61 mmol) and copper iodide (7 mg, 5% mol) and purge with nitrogen for 10 min. Add a solution of (S)-(2,4-dichlorobenzyl)-pyrrolidin-3-ylamine (238 mg, 0.97 mmol) in ethylene glycol (0.09 mL, 1.61 mmol) and isopropanol (1 mL). Stir at 80° C. for 4 days. Add water (2 mL) and extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph using preparative mass guided chromatography to give the title compound. Form the hydrochloride by essentially the procedure in Example 1 to give 1H NMR (400 MHz, MeOH-d4) δ 7.79 (1H, d, J=2.69 Hz), 7.63-7.70 (2H, m), 7.49 (1H, dd, J=8.31, 1.96 Hz), 7.34 (1H, d, J=8.80 Hz), 7.21 (1H, dd, J=8.80, 2.93 Hz), 4.48 (2H, s), 4.17-4.24 (1H, m), 3.72-3.79 (1H, m), 3.61-3.68 (2H, m), 3.38-3.44 (1H, m), 2.59-2.69 (1H, m), 2.32-2.33 (1H, m), 2.32-2.40 (1H, m), MS (ES): m/z=356 [M+].
Reaction SMILES: FC1C=CC(C([Cl:8])=O)=CC=1.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:48]=[CH:47][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]([N:35]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:36](=[O:39])[CH2:37]C)[CH2:27][CH:26]2[CH3:46])=[O:24])=[CH:21][CH:20]=1>>[Cl:8][C:43]1[CH:44]=[CH:45][C:40]([N:35]([C@H:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:25]([C:23](=[O:24])[C:22]3[CH:47]=[CH:48][C:19]([OH:18])=[CH:20][CH:21]=3)[C@@H:26]([CH3:46])[CH2:27]2)[C:36](=[O:39])[CH3:37])=[CH:41][CH:42]=1
Reactant: CCC(=O)N(c1ccccc1)C1CC(C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Oc1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide was prepared was made following general procedure C, substituting 3-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. Further elaboration to the phenol was done following the same procedure as described for (±)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide.
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.[NH:30]1[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:32]=[CH:31]1.COCC(O)C>>[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]([N:30]3[C:38]4[CH:37]=[CH:36][N:35]=[CH:34][C:33]=4[N:32]=[CH:31]3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: c1cc2[nH]cnc2cn1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(-n3cnc4cnccc43)nn12
Yield: 29.4 %

Procedure:
2-Methanesulfinyl-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 1H-Imidazo[4,5-c]pyridine (0.104 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 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 43.80 mg of 1-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine (mixture of regioisomers) as a lyophilized powder. (M+H)=343.7. 1H NMR (400 MHz, DMSO, d6) δ 9.35 (s, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=5.52 Hz), 8.09 (d, 1H, J=5.45 Hz), 7.81 (m, 2H), 7.57 (m, 1H), 7.32 (m, 3H), 7.23 (m, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])([O:3][CH2:4][CH3:5])=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:19][C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:22])[CH3:21]
Reactant: CCOC(=O)CCCCCCCC1CCCCC1=O
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CCCCCCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(7-carbethoxyheptyl)cyclohexan-1-one (Example 16) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C)=O)[CH2:3]1.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.F[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)NC2C=NC=CN=2)C1.F[C@H]1CN[C@H](C(NC2C=NC=CN=2)=O)C1>>[OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH2:3]1
Reactant: Nc1nccs1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Agent: O=C(Nc1cnccn1)[C@@H]1C[C@@H](F)CN1
Product: O=C(Nc1nccs1)[C@@H]1C[C@H](O)CN1

Procedure:
(2S,4S)-4-Hydroxy-N-(thiazol-2-yl)pyrrolidine-2-carboxamide 88A was prepared from (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate and 2-Amino thiazole as described for 65A and 65B. LC/MS [M+H]+: 214; Ret time (Method F): 0.35 min.
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([OH:9])=O.[CH3:22][CH2:23][O:24]CC>C(OC(=O)C)(=O)C>[C:23]([CH:10]1[C:11]2[C:12](=[CH:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=2)[C:13](=[O:14])[O:15][C:7]1=[O:9])(=[O:24])[CH3:22]
Reactant: COc1ccc(C(=O)O)c(CC(=O)O)c1
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(C(C)=O)C(=O)OC2=O
Reaction time: 16 h

Procedure:
Pyridine (5.0 ml, 62 mmol) is added slowly to suspension of 2-carboxymethyl-4-methoxy-benzoic acid (10 g, 48 mmol) in acetic anhydride (80 ml) at 0° C. After stirring for 16 h, ether (100 ml) is added. The resulting solid is collected and dried to give 10 g of 4-acetyl-6-methoxy-isochroman-1,3-dione.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[OH:3][C:4]1[CH:5]=[C:6]([C:10](=[O:12])/[CH:11]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)c1cccc(O)c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A 250 mL round-bottomed flask was charged sequentially aq. NaOH solution (NaOH 7.1 g/H2O 50 mL) and EtOH (40 mL). The solution was maintained below 10° C. in an ice bath. 1-(3-hydroxyphenyl)ethanone (20.0 g, 147 mmol) was added and stirred for 30 min at 10° C. To the resulting mixture was then added benzaldehyde (15 mL, 1.0 eq). After being stirred for additional 1 h at 10° C., the reaction mixture was stirred at room temperature for further 26 h. The solution was concentrated by rotary evaporation under reduced pressure. The residue was dissolved in EtOAc. The organic layer was washed with 3N HCl and H2O, dried over MgSO4, and concentrated in vacuo to obtain the desired product (32.5 g, 98%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[N:10]=[C:11]([C:15]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1cccc(SCc2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(SCc3ccccc3)n2)sc2ccccc12
Yield: 39.4 %

Procedure:
2-Benzylthio-6-cyanopyridine (1.63 g, 7.22 mmol) and methyl thiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml), and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (1.03 g, 44%) as white crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:18]1[N:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:20][CH:19]=1>>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([O:24][C:21]2[CH:22]=[N:23][C:18]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:19][CH:20]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)C(=O)NCc1ccc2[nH]ccc2c1
Product: CC(C)C(=O)NCc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-((1H-indol-5-yl)methyl) isobutyramide (intermediate 3) and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate 6) (0.103 g, 21.77%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](Cl)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7]([NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Br)cc21
Product: CC(NC1=NS(=O)(=O)c2cc(Br)ccc2N1)C(C)(C)C

Procedure:
Starting from 7-bromo-3-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.01 mmol) and 1,2,2-trimethylpropylamine (359 mg; 4.04 mmol) with the use of same procedure as in example 21 200 mg (54.9%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.35 (s, 1H, NH), 7.78 (d, 1H, H-8), 7.6 (dd, 1H, H-6), 7.12 (br d, 1H, H-5), 6.95 (br, 1H, NH), 3.72 (q, 1H, CH), 1.10 (d, 3H, CH3), 0.92 (s, 9H, 3×CH3); MS:EI/70eV: 361 (M+1), 304, 277, 236, 170, 116, 90, 44.