Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:7]2=[N:8][C:9]([CH3:16])=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=[C:6]2[CH2:5][CH2:4][CH2:3]1>ClCCl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:16][C:9]1[N:8]=[C:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]2=[CH:11][C:10]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc2c(nc1C)C(O)CCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc2c(nc1C)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
Methyl 8-hydroxy-2-methyl-5,6,7,8-tetrahydrocyclohexa[b]pyridine-3-carboxylate (3.95 g, 17.9 mmol) was dissolved in dichloromethane (80.0 ml), and the solution was mixed with activated manganese dioxide (23.29 g) and stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then purified by a short column chromatography (ethyl acetate) and recrystallization (ethyl acetate-ether) to obtain the title compound (975.1 mg, 24.9%) as pale yellow needle crystals.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].S(O)(O)(=O)=O.CS[C:15](=[NH:17])[NH2:16]>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:17]=[C:15]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:7])[N:16]=1
Reactant: NCCCCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C)nc(NCCCCCN)n1
Reaction time: 1 h

Procedure:
To 1,5-pentanediamine (1 g) dissolved in 10 ml water was added S-methylthiopseudourea sulfate (1.36 g) in 10 ml. of water. The amine solution was held at 45°-48° during the addition which took 1 hour. Stirring was continued for 8 hours. The volume was evaporated to about 10 ml under a stream of N2 on the steam bath. Ethanol (10 ml) and 10% NaHCO3 (10 ml) plus 10 ml of 2,4-pentanedione were added and the solution refluxed overnight. After brief cooling the solution was acidified to pH 1-2 and heated at 90° for 10 min. The cooled acidified mixture was then extracted thoroughly with ether, basified with 2N NaOH, and extracted with CHCl3. The combined CHCl3 extracts were evaporated to yield the crude product which was used without purification, wt 996 mg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.O1CCOCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: COc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 105 °C
Reaction time: 14 h
Yield: 55.3 %

Procedure:
1,4-Dioxane (100 ml) was added to a mixture of 2-chloro-4-methoxypyrimidine (20 gm), 4-aminobenzonitrile (16.33 gm) and p-toluene sulfonic acid (42.12 gm). The mixture was then heated to 100 to 110° C. and stirred for 14 hours. The solution was then cooled to room temperature and basified with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and then concentrated to obtain a residual solid. The residual solid obtained was slurried in isopropyl alcohol at room temperature for 30 minutes and filtered. The solid obtained was then dried to give 17.3 gm of 4-(4-methoxypyrimidin-2-ylamino)benzonitrile.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[N+:13]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7][CH2:6]2
Reactant: CNc1ccc2c(c1[N+](=O)[O-])CCCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc2c(c1N)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of N-methyl-1-nitro-5,6,7,8-tetrahydronaphthalen-2-amine (crude product from the previous step, 190 mg, 0.918 mmol) in MeOH (20 mL) was added 10% Pd on carbon (98 mg, 0.0918 mmol) under nitrogen, then replaced with hydrogen atmosphere (1 L). The resulting mixture was stirred at room temperature for 16 h. After filtration through Celite, the filtrate was concentrated and the residue was purified by prep-TLC (DCM/MeOH v/v 10:1) to give N2-methyl-5,6,7,8-tetrahydronaphthalene-1,2-diamine as a white solid (100 mg, 61% yield). ESI MS: m/z 177 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][O:5][N:6]=1.O.[NH2:10][NH2:11]>C(#N)C>[NH2:1][C:2]1[C:3]([C:7]([NH:10][NH2:11])=[NH:8])=[N:4][O:5][N:6]=1
Reactant: N#Cc1nonc1N
Reactant: NN
Solvent: O
Solvent: CC#N
Product: N=C(NN)c1nonc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of 4-amino-furazan-3-carbonitrile (0.50 g, 4.50 mmol) in acetonitrile (7.0 mL) was added hydrazine monohydrate (0.28 mL) dropwise. The solution was stirred at ambient temperature for 3 hours after which time a white solid precipitated. The solid was washed with acetonitrile and dried in vacuo to afford the title compound (0.60 g, 94%) as a white, fluffy solid. HPLC Method A Rt 0.18 min, m/z (ES+) (M+H)+ 143.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), (R)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown foam (69%).
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]1=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:3]([OH:20])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(OC)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
To a solution containing (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (160 mg, 0.57 mmol) in tetrahydrofuran (3 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (26 mg, 1.08 mmol) in water (3 mL). The mixture was stirred at 25° C. for 2.5 h. The mixture was then acidified with 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated. To afford (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (145 mg, 95%) as an off-white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](I)[CH3:18]>CC(=O)CC.O>[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12]
Reactant: CCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOc1ccc(C=O)cc1O
Yield: 43.5 %

Procedure:
Anhydrous potassium carbonate (2.25 g, 16.3 mmol) was added to 3,4-dihydroxybenzaldehyde (1.5 g, 10.8 mmol), in butanone (30 ml), at room temperature. The reaction was stirred for 10 min after which ethyl iodide (0.872 ml, 10.8 mmol) was added dropwise and the reaction was refluxed for 3 h. The reaction mixture was diluted with water and the product was extracted with dichloromethane (3×25 ml), the combined organic layers were dried over magnesium sulphate and reduced in vacuo. Purification by column chromatography (SiO2, petroleum:ether (40:60) with an increasing gradient of ethyl acetate) afforded 0.78 g (43%) of 3-hydroxy4-ethoxybenzaldehyde as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:7]([CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[N:6]=1)(=O)=O.[C-:26]#[N:27].[K+]>C(#N)C>[C:26]([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:7]([CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[N:6]=1)#[N:27]
Reactant: CCC(C)Cc1nc(S(C)(=O)=O)nc(C)c1-c1c(F)cc(F)cc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CCC(C)Cc1nc(C#N)nc(C)c1-c1c(F)cc(F)cc1F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g (1 mmol) of 2-methylsulfonyl-4-methyl-5-(2,4,6-trifluorophenyl)-6-(2-methylbutyl)pyrimidine (Example 1.3.) and 0.2 g (3 mmol) of potassium cyanide in 20 ml of acetonitrile p.a. was stirred at 20° C. for about 16 hours. The reaction mixture was then concentrated, the residue was taken up in methylene chloride and the organic phase was extracted with water. The organic phase was concentrated and the residue was purified by column chromatography using cyclohexane/methyl t-butyl ether mixtures. This gave 0.3 g (94%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH2:6])[CH3:2].[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=1)[C:23](O)=[O:24].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[NH:6][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][N:28]=[C:20]([Br:19])[CH:21]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
To methylene chloride (120 ml) are added 3-(3,4-dimethoxyphenyl)alanine ethyl ester (12.4 g), 2-bromoisonicotinic acid (10.9 g), 1-hydroxybenzotriazole monohydrate (8.23 g) and 1,3-dicyclohexylcarbodiimide (11.1 g), and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is concentrated. The residue is purified by silica gel chromatography (solvent; chloroform:acetone=10:1) to give N-(2-bromoisonicotinoyl)-3-(3,4-dimethoxyphenyl)alanine ethyl ester (13.9 g) as an oily product.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([OH:21])=O)=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:36][C:37]1[NH:41][N:40]=[N:39][N:38]=1>CN(C=O)C>[CH2:1]([S:5][C:6]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3=[CH:16][C:17]([C:19]([NH:36][C:37]4[NH:41][N:40]=[N:39][N:38]=4)=[O:21])=[N:18][N:10]3[C:9](=[O:22])[C:8]=2[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1ccc2[nH]c3cc(C(=O)Nc4nnn[nH]4)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-butylthio-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (1.9 g; 6 mmole), DMF (25 ml), 1,1'-carbonyl-diimidazole (2.19 g; 13.5 mmole) and 5-amino-1H-tetrazole, monohydrate (0.70 g; 6.8 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-7-butylthio-9-oxo-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide, with 1H-imidazole (3:1) (0.4 g); mp 285° (d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:25])[NH:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:37].O>C(O)C>[C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][N:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17](=[O:25])[NH:18][CH2:19][C:20]([O-:22])=[O:21])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Na+:37]
Reactant: CCOC(=O)CNC(=O)N(Cc1ccc(C=NNC(=O)OC(C)(C)C)cc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NN=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.78 g (5.74 mmol) of ethyl (3-(4-(tert-butyloxycarbonylaminoiminomethyl)benzyl)-3-benzyloxyureido)acetate in 50 ml of ethanol are treated with 0.23 g (5.74 mmol) of NaOH and 1.2 ml of water and the mixture is stirred at room temperature for 18 h. The solvent is removed in vacuo and the residue is freeze-dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:23]1CCOCC1.ClC(OCC(C)C)=O.N>O1CCCC1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:17][CH2:18][C:19]([NH2:23])=[O:21])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCC(N)=O)CCC1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Next, anhydrous tetrahydrofuran (7 ml) was added to 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid (0.59 g, 2.0 mmol), and the mixture was stirred at −78° C. N-Methylmorpholine (0.22 ml, 2.0 mmol) and then a solution of isobutyl chloroformate (0.38 ml, 2.9 mmol) in tetrahydrofuran (3 ml) were added to the mixture. After one hour, a 28% aqueous ammonia solution (6.0 ml, 9.8 mmol) was added thereto, and the whole was stirred for 1.5 hours. Chloroform (50 ml) was added to the reaction mixture, the temperature was raised to room temperature, and the whole was washed with a saturated aqueous sodium hydrogencarbonate solution (20 ml) and saturated brine (20 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.34 g (58%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionamide as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH3:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:35]2[CH2:36][CH2:37][CH2:38][CH:34]2[CH3:33])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Reactant: CC1CCCN1
Product: CC1CCCN1c1ccc(C(=O)c2sc(Nc3ccc(N4CCN(C)CC4)cc3)nc2N)cc1[N+](=O)[O-]

Procedure:
This compound was prepared from the compound of Example 15 and racemic 2-methylpyrrolidine (Alfa Aesar) by the procedure used in Example 57. Mass spectrum (ES) MH+=522.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][C:21](Br)=[C:22]([Br:25])[C:23]=2[CH3:24])[N:16]([CH3:27])[N:15]=1.O>C1COCC1>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[S:20][CH:21]=[C:22]([Br:25])[C:23]=2[CH3:24])[N:16]([CH3:27])[N:15]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)sc(Br)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)csc1-c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
n-Butyl lithium (6.04 mL, 2.5 mmol) was slowly added over a 15 min period to 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4,5-dibromothien-2-yl) 1-methyl [1,2,4] triazole (7.0 g) in THF (100 mL) at −70° C. under a nitrogen atmosphere and stirred for 1.0 h. After the addition of the distilled water, the reaction was allowed to warm to 25° C. The reaction mixture was extracted with diethyl ether (3×100 mL). The combined ether extracts was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to crude solid. This was chromatographed on silica gel (EtOAc/Hexane, 1:1) to give 5.0 g (86% yield) 3-(2-chloro-6-fluorophenyl)-5-(3-methyl-4-bromothien-2-yl) 1-methyl [1,2,4] triazole as white solid. MP 111-112° C. ; Anal. Calcd. For C14H10BrClFN3S: C, 43.49; H, 2.61; N, 10.87; S, 8.29. Found; C, 43.79; H, 2.66; N, 10.95; S, 8.28.
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11][CH2:10]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:11]1[C:9]2([CH2:12][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:14][CH2:15][NH:8]2)[CH2:10]1
Reactant: c1ccc(CN2CCN(c3ncnc4[nH]ccc34)CC23CC3)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reaction time: 0.25 h
Yield: 165.8 %

Procedure:
To 4-(4-benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 22) (50 g, 78.36 mmol) in MeOH, was added 10% Pd/C (20 g) and HCOONH4 (98 g, 783.69 mmol) and the reaction mixture was heated to reflux for 30 min. The reaction mixture was filtered through celite bed and washed with MeOH and concentrated under reduced pressure. The crude compound was treated with 50% NaOH solution (200 ml) and stirred for 15 min and solid was obtained by filtration. And the solid was wash with 50 ml of water and dried under vacuum. The crude compound (33 g) in acetone (10 times) was heated to reflux for 30 min. The reaction mixture was cooled and filtered and the solid was washed with acetone to afford the title compound as a solid (29.78 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](C(O)=O)=[C:6]2[CH3:19].Cl>N1C2C(=CC=CC=2)C=CC=1.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH:7]=[C:6]2[CH3:19]
Reactant: COc1cc2c(C)c(C(=O)O)[nH]c2cc1C(F)(F)F
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COc1cc2c(C)c[nH]c2cc1C(F)(F)F
Yield: 53 %

Procedure:
To a solution of 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid (2.0 g, 7 mmol) in 5 ml quinoline was added copper powder (50 mg), and the reaction mixture was heated to reflux for 1.5 hours. Copper powder (50 mg) was added, and the reaction mixture was refluxed for 1 hour. The reaction mixture was cooled, diluted with EtOAc, poured into 50 ml 6 N HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed (10% EtOAc/Hexanes) to give 5-Methoxy-3-methyl-6-trifluoromethyl-1H-indole (850 mg, 51% ) as a solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]CC([O:23][CH2:24][CH3:25])=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(C)C>[ClH:19].[C:13]1([CH2:12][N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][C:24]2=[O:23])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCl
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
A mixture of N,N'-dibenzylethylenediamine (24.0 g., 0.1 mole), ethyl chloroacetate (V, 24.51 g., 0.2 mole), anhydrous sodium carbonate (10 g., 0.094 mole) in ethanol (250 ml.) is heated under reflux for 20 hours. The ethanol is removed under reduced pressure and the residue is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is dissolved in isopropanol (200 ml.) and acidified with ethereal hydrogen chloride. The precipitate of 1,4-bis(phenylmethyl)piperazinone hydrochloride is filtered off and recrystallized from isopropanol, m.p. 209°-212°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22].C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>C1COCC1.Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[C:16]([F:20])[C:15]=1[CH:21]([F:23])[CH3:22]
Reactant: CC(F)c1c(F)cccc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(F)c1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
A 2.5M solution of n-butyllithium (13 mL, 33 mmol) was added to a stirred solution of diisopropylamine (5.0 mL, 35 mmol) in THF (50 mL) at −78° C. The resulting colorless solution was stirred at −78° C. for 20 min, warmed to 0° C. for 20 min, and then cooled back to −78° C. for 20 min A solution of 1-chloro-3-fluoro-2-(1-fluoroethyl)benzene (4.8 g, 27 mmol, 1.0 equiv) in THF (20 mL) at −78° C. was transferred to the base solution via cannula. The resulting dark brown solution was stirred at −78° C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.3 mL, 41 mmol, 1.5 equiv) was added and the brown solution was slowly warmed to 23° C. over 20 h. The reaction mixture was diluted with 0.1M hydrochloric acid (300 mL) and extracted with dichloromethane thrice. The combined organic extracts were dried, filtered and concentrated by rotary evaporation to afford the title compound as a brown oil that solidified into a semi-solid upon standing (7.7 g, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.62 (m, 1H), 7.17 (m, 1H), 6.13 (dq, 1H, J=6, 46 Hz), 1.75 (ddd, 3H, J=1, 7, 23 Hz), 1.36 (s, 12 H).
Reaction SMILES: [Li][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:8]1([P:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH4+].[Cl-]>C1COCC1>[C:25]1([P:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][CH:22]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:21]=[CH:20]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=CC(c2ccccc2)Nc2c1cccc2P(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
PhLi (0.56 mL, 1.8M in di-n-butyl ether, 1 mmol) was added to a stirred solution of 8-diphenylphoshinoquinoline (1) (156 mg, 0.5 mmol) in dry THF (5 mL) at −78° C. and the solution was stirred at 0° C. for 10 minutes. The solution was then cooled to −78° C., saturated aqueous NH4Cl solution (10 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 4 (196 mg) quantitatively as a yellow oil. 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.3 (m, 15H, Ph-H), 6.92 (d, 1H, J=7.2 Hz, C5—H), 6.69 (ddd, 1H, J=7.2, 6.0, 1.2 Hz, C7—H), 6.54 (t, 1H, J=7.2 Hz, C6—H), 6.38 (d, 1H, J=9.6 Hz, C4—H), 5.64 (dd, 1H, J=10.0, 4.0 Hz, C3—H), 5.44 (bs, 1H, N1—H), 5.15 (d, 1H, J=7.2 Hz, C2—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 146.5 (d, J=19.2 Hz), 145.1, 135.4 (d, J=8.1 Hz), 135.3 (d, J=7.1 Hz), 134.5, 133.7 (d, J=18.2 Hz), 133.6 (d, J=19.2 Hz), 133.4 (d, J=19.2 Hz), 127.3, 128.7-128.3 (m), 127.1, 126.0, 125.2, 124.5, 119.1, 117.1, 116.1 (d, J=8.1 Hz), 57.6 ppm; 31P NMR (161.97 MHz, CDCl3) δ −23.8 ppm.