Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[Cl:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(I)cc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Clc1ncnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
In a 100 mL-volume glass vessel equipped with a stirrer, a thermometer and a reflux condenser were placed 20.0 g (73.5 mmol) of 6-iodoquinazolin-4-one, 13.5 g (88.2 mmol) of phosphorus oxychloride, and 60 mL of toluene in a nitrogen atmosphere. While the mixture was stirred at room temperature, 8.92 g (88.2 mmol) of triethylamine was slowly added. The resulting mixture was heated to 75° C., and the reaction was carried out for 2 hours. After the reaction was complete, the reaction mixture was cooled to 0° C. and stirred for one hour. Thus precipitated pale yellow crystalline product of 6-iodo-4-chloroquinazoline was collected by filtration. Subsequently, the crystalline product was placed in 100 mL of aqueous sodium hydroxide (1 mol/L), and the aqueous mixture was stirred for 30 minutes at room temperature. The crystalline product was collected by filtration, washed with 120 mL of water, and dried under reduced pressure, to give 19.3 g (isolated yield: 90%, purity 99.3% in terms of area percentage determined by high performance liquid chromatography) of 6-iodo-4-chloroquinazoline as a yellowish crystalline product.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([S:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(Sc2ccncc2)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(Sc2ccncc2)c2ccccc2c1=O

Procedure:
The product from Example 191B and (4-chlorophenyl)acetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.44-8.35 (m, 3H), 8.05-7.92 (m, 3H), 7.44-7.35 (m, 4H), 7.29-7.22 (m, 2H), 3.71 (s, 2H); MS (DCI+) M/Z 423 (M+H)+.
Reaction SMILES: [CH:1](/[C@:11]1([CH3:22])[C@H:18]2[CH2:19][C@H:14]([C@@H:15]([CH3:21])[C:16](=[O:20])[CH2:17]2)[O:13][O:12]1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>C(OCC)(=O)C.[Pt]>[CH2:1]([C@@:11]1([CH3:22])[C@H:18]2[CH2:19][C@H:14]([C@@H:15]([CH3:21])[C:16](=[O:20])[CH2:17]2)[O:13][O:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCC/C=C/[C@@]1(C)OO[C@@H]2C[C@H]1CC(=O)[C@@H]2C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCC[C@]1(C)OO[C@@H]2C[C@H]1CC(=O)[C@@H]2C

Procedure:
3.59 g of (1R,4S,5S,8R)-4-[(E)-1-decenyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one [obtained in accordance with Example 2(e)] dissolved in 180 ml of ethyl acetate are hydrogenated for about 1.25 hours with hydrogen over 360 mg of 5 percent platinum/charcoal at 1.013·105Pa. The end point of the reaction is determined by gas-chromatographic analysis. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated. The residue is purified by column chromatography on silica gel while eluting with hexane/ethyl acetate (3:1). There is obtained (1R,4S,5S,8R)-4-decyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]-nonan-7-one as a colourless oil, which crystallizes from hexane [m.p. 57°].
Reaction SMILES: [CH2:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=2)[C:13]([CH2:21][C:22]([NH2:24])=[O:23])=[C:12]1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H-].[Na+].Br[CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]([CH3:25])=[C:13]2[CH2:21][C:22]([NH2:24])=[O:23])[CH3:36]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Yield: 55 %

Procedure:
[4-[[3-(2-Amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanois acid ethyl ester. 1-Decyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (310 mg, 3.35 mmol) was reacted with 96 mg (2.4 mmol) of 50% NaH/mineral oil and then 0.32 mL (2.4 mmol) of ethyl 4-bromobutyrate as described in Example 50, Part D to give a product that was chromatographed on silica gel (eluted with 3% MeOH/methylene chloride) to give 590 mg (55% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 93-95° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[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.O.[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:23][CH2:27][CH:29]1[O:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(OCC3CO3)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 6.1 g. of 3,4-dibenzyloxyphenol in 10 ml. of water and 1.53 g. of potassium hydroxide pellets is added 5.6 g. of epichlorohydrin in 60 ml. of ethanol. The solution is stirred at room temperature for 24 hours and then concentrated in vacuo. The residue is suspended in water and the mixture extracted with ether. The ether extracts are dried to yield 3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH3:21])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:20][CH3:21])[CH2:12][NH:11][CH2:10]1
Reactant: COC1(c2cccc(F)c2F)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(c2cccc(F)c2F)CNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred solution of tert-butyl 3-(2,3-difluorophenyl)-3-methoxyazetidine-1-carboxylate (0.7 g, 2.34 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (3 ml, 40 mmol). The resulting mixture was stirred at ambient temperature for 2 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1). The solvents where evaporated to give (0.16 g, 64%) of the title compound. The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 141-142° C. MS m/z (relative intensity, 70 eV) 199 (M+, 1), 170 (bp), 169 (97), 140 (82), 127 (47).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30]2)[CH2:26][CH2:25]1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:15])[CH2:10][CH2:11][N:24]2[CH2:29][CH2:28][C:27]3([C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH2:26][CH2:25]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C[C@@H](CCN1CCC2(C=Cc3ccccc32)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Yield: 78.6 %

Procedure:
To a solution of 3.46 g (10 mmol) of 3-(S)-(3,4-dichlorophenyl)-4-(t-butoxycarbonyl-methylamino)butanal (Example 1) in 20 mL of methanol were added 3.11 g (14 mmol) of spiro(1H-indene-1,4'-piperidine) hydrochloride and 3 g of powdered 4 Å molecular sieves. After 15 min a solution of 2.52 g (40 mmol) of NaCNBH3 in 30 mL of THF was dropwise added. Some gas evolution was observed. After stirring the reaction overnight, the mixture was filtered through a pad of celite, the reaction flask and the pad were rinsed with methanol. The filtrate was concentrated to approximately 10 ml and the residue was partitioned between saturated NaHCO3 and Et2O:EtOAC. The organic layer was washed with water, brine and dried over NA2SO4. The filtrate was concentrated and the residue was chromatographed on a flash column using a gradient of 49:49:2 to 98:0:2 EtOAc: Hexane: triethylamine to furnish 4.05 g (79%) of the title compound as a foam.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)(=O)=O.[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([OH:48])[CH:45]=[CH:46][CH:47]=1)=[O:41]>>[CH3:38][N:39]([CH3:49])[C:40]([C:42]1[CH:43]=[C:44]([CH:45]=[CH:46][CH:47]=1)[O:48][C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][C:23]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:6]=1)=[O:41]
Reactant: CCOC(=O)CNc1nc(S(C)(=O)=O)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CN(C)C(=O)c1cccc(O)c1
Product: CCOC(=O)CNc1nc(Oc2cccc(C(=O)N(C)C)c2)nc(Oc2cc(C#N)ccc2OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (M), prepared as described below in Preparation 4, is treated with 3-(dimethylaminocarbonyl)phenol, a compound of formula (B) to afford 2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (N).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([OH:11])=[O:10].[CH2:12](O)[CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:12]([O:10][C:9]([CH:4]1[CH2:5][NH:6][CH2:7][CH2:8][NH:3]1)=[O:11])[CH3:13]
Reactant: CCO
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CNCCN1
Yield: 26 %

Procedure:
A mixture of 2-piperazinecarboxylic acid dihydrochloride (5.06 g, 0.025 mol), ethanol (100 ml) and concentrated sulphuric acid (6.0 ml) was heated at reflux temperature for 6 days. Toluene (10 ml) was added, and the resulting mixture was concentrated in vacuo to 213 of its original volume. Cold, saturated aqueous potassium carbonate (80 ml) was added and the mixture was extracted with toluene (3×100 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuc, affording 1.0 g (26%) of 2-piperazinecarboxylic acid ethyl ester as an oil. The oil crystallised upon standing at room temperature.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][O:10][C:11]1[C:15](OC)=[N:14][S:13](=[O:18])[N:12]=1>CO>[CH3:9][O:10][C:11]1[C:15]([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:14][S:13](=[O:18])[N:12]=1
Reactant: NCc1cccnc1
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)N=C1NCc1cccnc1

Procedure:
A solution of 3-aminomethylpyridine (2.02 g; 18.7 mmoles) in 80 ml of methanol was added dropwise over 40 minutes to a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (3.03 g; 18.7 mmoles) in 150 ml of methanol, to produce a methanol solution of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:31])[CH2:23][N:24]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[N:25]2)[CH2:18][CH2:17]1.ClC(Cl)C.CC1C=CC(S(O)(=O)=O)=CC=1>>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:31])[CH2:23][N:24]2[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[N:25]2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3C(=O)Nc3ccccc3N)CC2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ccccc3-c3nc4ccccc4[nH]3)CC2)n1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
The N-(2-amino-phenyl)-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-benzamide (0.050 g, 0.116 mmol) is dissolved into 2 mL of dichloroethane and placed in a microwave tube. To this is added a catalytic amt. of p-TsOH. The mixture is heated in a microwave at 130° C. for 20 min and then 160° C. for 30 min. The reaction mixture is concentrated to dryness and the product is purified using a Gilson Prep HPLC system eluting with 20%-100% CH3CN/H2O) to give 43 mg of desired product. Impure fractions are concentrated and purified using a SiO2 prep plate eluting with (5% MeOH/CH2Cl2) to give an additional 17.5 mg of 1-{4-[2-(1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-yl}-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH:49]([CH:54]([CH3:56])[CH3:55])[C:50]([O:52][CH3:53])=[O:51]>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH:49]([C:50]([O:52][CH3:53])=[O:51])[CH:54]([CH3:56])[CH3:55])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)C(C)C
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCc1nn(C(C(=O)OC)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 56 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with methyl 2-bromo-3-methylbutyrate was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (50 mL for 0.324 mmole, eluted using 0.5% MeOH/CH2Cl2) to give the desired material as a white foam in 56% yield, homogeneous by TLC in 5% MeOH/CH2Cl2.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[NH:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][O:13][CH2:12][CH:11]([CH3:15])[N:10]([C:25](=[O:26])[C:24]3[CH:28]=[C:20]([CH3:19])[CH:21]=[CH:22][C:23]=3[N:29]3[N:33]=[CH:32][CH:31]=[N:30]3)[CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(OCC2CNC(C)COC2)ccc1F
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC(COc3ccc(F)c(C)c3)COCC2C)c1

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-7, 13 mg, 0.051 mmol, 1 equiv), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (16 mg, 0.077 mmol, 1.5 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 15 mg, 0.077 mmol, 1.5 equiv), 1-hydroxybenzotriazole (12 g, 0.077 mmol, 1.50 equiv) and triethylamine (21 uL, 0.15 mmol, 3.0 equiv) in DMF (5 mL) was stirred at 23° C. for 20 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (100% hexanes initially, grading to 40% hexanes in EtOAc) to provide 6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-oxazepane (4-8) as a mixture of diastereomers. LRMS m/z (M+H) 439.0 found, 439.2 required.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)=[O:7]>C(OCC)(=O)C>[CH3:5][S:6]([C:8]1[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=1)=[O:7]
Reactant: O=C(Cl)Cl
Reactant: CS(=O)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CS(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfinyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1.[OH-].[K+].Cl>CO>[F:1][C:2]([F:26])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(OC)c(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)O)cc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Ethyl N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamate (51 mg) obtained in step E was dissolved in 2 mL of methanol, and 0.8 mL of a 20% aqueous solution of potassium hydroxide was added. The resulting solution was stirred for 30 minutes at 80° C., and then cooled to room temperature. One M hydrochloric acid (3 mL) was used to adjust the solution to pH of about 3. Then, the resulting aqueous solution was extracted with ethyl acetate. The respective organic layers were combined, whereafter the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 48 mg (100%) of N-(4-trifluoromethoxyphenyl)-4-methoxyisophthalamic acid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:9]([C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:7]=2)[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:22])=[C:19]([NH2:20])[NH:21][C:19]=1[NH2:20])=[O:22])[CH3:15]
Reactant: CCOC(=O)c1cccc(C=O)c1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1cccc(C(=O)OCC)c1
Yield: 32 %

Procedure:
Upon boiling a solution of 8.9 g 3-carbethoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 100 ml ethanol for 2 hours, 2,6-diamino-4-(3-carbethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 191° C (ethanol) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1N)[NH:28][C:27](=[O:33])[CH2:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:33])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Nc1cc2c(cc1Br)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 39.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-mopholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 39.8%) as a red solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].C1(C)C=CC=CC=1>[CH3:27][Si:28]([C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1)([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(Br)ccc1-2
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1)c1cc(C#C[Si](C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
A mixture of bromide 5 (0.3 g, 0.73 mmol), trimethylsilylacetylene (0.143 g, 1.46 mmol) and bis(triphenylphosphine)-palladium-(II) acetate (55 mg, 0.073 mmol) in a mixed solvent system of toluene (20 mL) and anhydrous TEA (50 mL) was heated to reflux under argon. See, Liu, et al., 1996; Austin, et al., 1981; Heck, 1985. After stirring for 12 hours at reflux, the mixture was cooled to room temperature and the precipitate which formed was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a saturated aqueous solution of NaHCO3 (20 mL), and extracted with CHCl3 (3×25 mL). The combined extracts were washed with brine and dried (Na2SO4). After removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, EtOAc) to afford 6 (XLiXHeII-048) as a white solid (0.29 g, 93%). This benzodiazepine can also be obtained from 2 in 45% yield by following the same procedure 6 (XLiXHeII-048): mp: 170-172° C.; IR (KBr) 2958, 2152, 1718 cm−1; 1H NMR (CDCl3) δ 0.23 (s, 9H), 1.42 (t, 3H, J=7.2 Hz), 4.04 (d, 1H, J=12.6 Hz), 4.41 (m, 2H, J=7.2 Hz), 6.23 (d, 1H, J=12.6 Hz), 7.35-7.55 (m, 7H), 7.73 (dd, 1H, J=8.3 Hz and 1.9 Hz), 7.93 (s, 1H); MS (EI) m/e (relative intensity) 427 (M+, 76), 412 (5), 381 (55), 353 (100) 303 (10), 287 (7). Anal. Calcd. for C25H25N3O2Si.⅓EtOAc: C, 69.22; H, 6.01; N, 9.20. Found: C, 68.87; H, 5.81; N, 9.37.