Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:11]([Cl:21])[CH:10]=1)[CH2:4][CH3:5].Cl.Cl>CCOCC>[Cl:21][C:11]1[CH:10]=[C:9]([CH:8]=[CH:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH:14]=[CH:13][C:12]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCN(CC)C/C=C/c1ccc(C2CCCCC2)c(Cl)c1
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)CC=Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
81 g of the compound produced in step (b) were dissolved in 500 ml of toluene and, to the solution so produced, was added a solution of 76 g of p-toluenesulphonic acid in the minimum quantity of water. The mixture was heated under reflux for about 20 hours, continuously removing the water formed. At the end of this time, the solution was cooled and poured into 2 liters of water, to which ammonia was added until the solution became alkaline. The organic phase was then separated, washed with water and dried with sodium sulphate. 66 g (yield 86%) of 3-chloro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene (hereinafter referred to as compound 933 CB) were obtained in the form of a light brown oil. This was dissolved in ether and reacted with a sufficient quantity of hydrochloric acid dissolved in the same solvent to produce 67 g of the hydrochloride having a melting point of 161° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][CH:5]([CH3:7])[CH3:6])[OH:3].[OH-].[Na+].[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35]Br)[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13].CN(C=O)C>CC(C)=O>[CH2:12]([C@H:14]1[CH2:19][C@H:18]2[C@H:20]3[C@H:29]([CH2:30][CH2:31][C@:16]2([CH3:17])[C@H:15]1[O:33][C:34](=[O:37])[CH2:35][O:8][C:1](=[O:9])[CH:2]([OH:3])[CH2:4][CH:5]([CH3:7])[CH3:6])[C@@H:28]1[C:23](=[CH:24][C:25](=[O:32])[CH2:26][CH2:27]1)[CH2:22][CH2:21]3)[CH3:13]
Reactant: CC(C)CC(O)C(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(O)CC(C)C
Yield: 96.3 %

Procedure:
In 2.0 ml of acetone is dissolved 0.26 g of leucic acid, and 1.0 ml of 2N-NaOH is added, followed by addition of 0.44 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 15 ml of DMF. The mixture is refluxed for 3 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is then subjected to column chromatography. Following passage of 50 ml of diisopropyl ether-n-hexane (1:1), elution is carried out with 200 ml of diisopropyl ether. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.475 g of the above-identified compound as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2CCCCN2CC(C2C=CC=C(Br)C=2)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C([O:31]CC)C>>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:31])[CH3:8]
Reactant: CC(CN1CCCCC1CC1CCCCC1)c1cccc(Br)c1
Reactant: CCOCC
Agent: [Li]CCCC
Product: CC(=O)c1ccccc1

Procedure:
Following a procedure similar to that described in Example 3, 37.8 g. (0.1 mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted with 0.18 mole of n-butyl lithium in diethyl ether and the resulting lithio derivative reacted directly with 27 g. (0.23 mole) of acetophenone to give 11.8 g. of 2-cyclohexylmethyl-1-{2-[3-(α-hydroxy-α-methylbenzyl)phenyl]propyl}piperidine as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36](O)=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:36]([C:31]3[C:30]([C:27]4[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][CH:28]=4)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:37])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: Cc1ccc(-c2ccccc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)cc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 4′-methyl-biphenyl-2-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([NH:30][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1nc(Cl)ncc1-c1nnn[nH]1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
In a microwave tube, 2-chloro-5-(1H-tetrazol-5-yl)pyrimidin-4-amine (200 mg, 1.0 mmol) was dissolved into 3 mL of dioxane and DIPEA (1.5 mmol, 1.5 eq.). After the addition of benzylamine (5.0 mmol, 5.0 eq.), the tube was capped and irradiated in a CEM Discover microwave reactor to 120° C. for a total of 60 minutes in three 20 minutes intervals. LC/MS was taken every 20 minutes to follow the disappearance of starting material. After the complete consumption of the starting material, the reaction was cooled to room temperature and a precipitate formed. This solid was collected by filtration, washed several times with water, then with hot EtOAc. It was dried under vacuum to afford 27 mg of desired product. This material was carried forward without further purification. MS (EI) for C12H12N8: 269 (M+H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:19][CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>>[C:1]([NH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Reactant: BrCCCOC1CCCCO1
Product: CCCCCC(=O)Nc1ccc2ccn(CCCOC3CCCCO3)c2c1
Yield: 81 %

Procedure:
6-Hexanamidoindole was alkylated with 2-(3-bromopropoxy)tetrahyro-2H-pyran using a similar procedure to that described in Example 23 to give 2-[3-(6-hexanamidoindol-1-yl)propoxy]tetrahydro-2H-pyran in 81% yield as an oil, which was used without characterisation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:31].[OH-]>>[NH2:31][C:2]1[N:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=3[F:30])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1cccc(-c2ncsc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: [OH-]
Product: Nc1nccc(-c2scnc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)n1
Temperature: 140 °C
Yield: 64.7 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (0.1 g, 0.2 mmol) was taken up in 2 mL NH4OH and heated to 140° C. for 20 min in a microwave reactor. The solvent was removed under reduced pressure and the residue was taken up in EtOAc and washed with 2 mL of 0.1 N HCl (aq). The organic layer was dried over Na2SO4 and evaporated onto silica gel. Purification by ISCO chromatography (0 to 50% EtOAC in DCM) afforded the title compound (62 mg, 0.139 mmol, 64.7% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H), 9.16 (s, 1H), 7.94 (d, J=5.1 Hz, 1H), 7.59-7.69 (m, 1H), 7.32 (t, J=7.9 Hz, 1H), 7.16-7.27 (m, 5H), 6.78 (s, 2H), 5.99 (d, J=5.3 Hz, 1H). MS (ESI): 446 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: [H][H]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 64 %

Procedure:
A mixture of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 21, 1.70 g, 4.52 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (23 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 20 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (50 mL) and adjusted to pH 12 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from ethanol. The crystals were isolated and dried under vacuum at 65° C. to afford 1.10 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 226-229° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C:20]3=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]3[CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.Cl>CO>[O:26]=[S:22]1(=[O:25])[CH2:23][CH2:24][N:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:20]2=[N:21]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2CCCN3CCS(=O)(=O)N=C23)cc1
Agent: Cl
Solvent: CO
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A mixture of (9S)-9-(4-((tert-butyldimethylsilyl)oxy)phenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (13.7 g) and 6 M HCl aq. (17.4 mL) in MeOH (350 mL) was stirred at 60° C. for 2 hr. After cooling to room temperature, the precipitate was collected and washed with MeOH to give the title compound (8.20 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl.[CH3:16][N:17]([CH3:32])[S:18]([C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH2:28]Cl)=[N:27][C:23]=2[CH:22]=1)(=[O:20])=[O:19]>CN(C)C=O>[CH3:32][N:17]([CH3:16])[S:18]([C:21]1[CH:31]=[CH:30][C:24]2[NH:25][C:26]([CH2:28][O:10][C:8]3[CH:9]=[C:2]([F:1])[C:3]([CH:4]=[O:5])=[CH:6][C:7]=3[O:11][CH3:12])=[N:27][C:23]=2[CH:22]=1)(=[O:19])=[O:20]
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: CN(C)S(=O)(=O)c1ccc2[nH]c(CCl)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1nc2cc(S(=O)(=O)N(C)C)ccc2[nH]1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 16.6 %

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 0.38 g, 2.2 mmol) was dissolved in N,N-dimethylformamide (30 mL) and sodium hydride 60% dispersion in mineral oil (120 mg) was added. After 20 minutes, 2-chloromethyl-1H-benzoimidazole-5-sulfonic acid dimethylamide hydrochloride salt (217, 0.559 g, 1.80 mmol) was added to the mixture. The reaction was stirred at 60° C. overnight. The solvent was removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of ethyl acetate (20-100%) in hexane to provide the desired compound (218, 0.122 g, 17%).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:20]([CH3:22])[CH3:21])=[CH:11][C:12]=2/[C:14](/[CH3:19])=[C:15](/[F:18])\[CH2:16][OH:17])[C:7]([CH3:24])([CH3:23])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C[N+]1([O-])CCOCC1>>[F:18]/[C:15](=[C:14](/[C:12]1[CH:11]=[C:10]([CH:20]([CH3:21])[CH3:22])[CH:9]=[C:8]2[C:13]=1[N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][C:7]2([CH3:24])[CH3:23])\[CH3:19])/[CH:16]=[O:17]
Reactant: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)CO)c21
Agent: C[N+]1([O-])CCOCC1
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(/C(C)=C(/F)C=O)c21

Procedure:
Following General Procedure G, (E)-3-(1-n-propyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-but-2-en-1-ol (Intermediate 20, 1.34 g, 4.04 mmol) and N-methylmorpholine N-oxide (947 mg, 8.08 mmol) were reacted to give the title compound as a bright yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:23])[N:15]=2)=[O:13])[CH2:3]1.[CH3:24][C:25]1[S:26][C:27]([C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)=[C:28]([C:30](O)=[O:31])[N:29]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:30]([C:28]3[N:29]=[C:25]([CH3:24])[S:26][C:27]=3[C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[O:31])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:23])[N:15]=2)=[O:13])[CH2:3]1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3nn(C)c4ccccc34)[C@H]2C1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2nn(C)c3ccccc23)c1

Procedure:
prepared by reaction of 1-methyl-1H-indazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][Si:14]([CH3:31])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.CI>CCCCCC.O1CCCC1>[CH3:31][Si:14]([CH3:13])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:1])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)NC(C)C
Reactant: CC(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Distilled diisopropylamine (1.98 g, 19.6 mmol) was added to dry tetrahydrofuran (10 ml) under anhydrous conditions. To the stirred solution at 0° C. was added 1.55M n-butyllithium (12.6 ml, 19.6 mmol) in hexane dropwise. After 15 minutes a solution of the compound (1a) (2.2 g, 7.8 mmole) in tetrahydrofuran (10 ml) was added dropwise at 0° C. The reaction mixture was stirred for 1 hour at ambient temperature 30 minutes at 50° C. and then cooled to 0° C. Methyl iodide (2.78 g, 19.6 mmol) was added dropwise, and the reaction mixture stirred at ambient temperature for about 16 hours. The reaction was quenched with saturated ammonium chloride (20 ml) and acidified with 3N hydrochloric acid. The reaction mixture was extracted with diethyl ether (3×100 ml), the extracts combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give a tan solid. This compound was chromatographed on a 5×15 cm column of silica gel eluted with 5 percent isopropanol/hexane to yield the desired product as a solid, m.p. 78-80° C.
Reaction SMILES: [IH:1].[C:2]1([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:9][C:10](=[NH:13])SC)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24]N>ClC1C=CC=CC=1Cl>[IH:1].[C:2]1([CH:8]([NH:9][C:10]2[N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)NC(c1ccccc1)c1ccccc1
Reactant: CNCCCN
Agent: I
Solvent: Clc1ccccc1Cl
Product: CN1CCCN=C1NC(c1ccccc1)c1ccccc1

Procedure:
To 38.43 grams (0.10 mole) of 1-diphenylmethyl-2-methyl-2-thiopseudourea hydroiodide in 270 milliliters of o-dichlorobenzene was added 8.81 grams (0.10 mole) of N-methyl-1,3-diaminopropane, and the resulting mixture was allowed to reflux for about 21 hours to produce the desired 2-diphenylmethylamino-1,4,5,6-tetrahydro-1-methylpyrimidine product. Thereafter, the mixture was allowed to cool, the solvent was decanted off and isopropanol was added to the residue to obtain 35.0 grams (86 percent yield) of a 2-diphenylmethylamino-1,4,5,6-tetrahydro-1-methylpyrimidine hydroiodide salt. After successive recrystallizations from acetone-ether and acetone-isopropanol, a purified product was obtained having a melting point (151°) 169°-171° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.[Cl:23]NC(=O)CCC(N)=O>C1COCC1.CCCCCC>[Br:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][C:19]([Cl:23])=[CH:20][C:16]=2[CH:15]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: Brc1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Clc1cc2cc(Br)ccc2s1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
n-Butyl lithium (0.64 ml, 1.2 mmol) was added drop wise to a solution of diisopropyl amine (0.25 mL, 1.5 mmol) in dry THF at −78° C. under nitrogen atmosphere over a period of 5 minutes. The reaction mixture was stirred at −20° C. for 30 minutes. To this was added 5-bromo-benzo[b]thiophene (200 mg, 0.938 mmol) in dry THF at −78° C., continued stirring for a further 30 minutes at −78° C., followed by the addition of N-chlorosuccinamide (225 mg, 1.68 mmol) in dry THF at −78° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC (100% hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was dried over sodium sulfate and concentrated to afford the crude product. Purification by column chromatography on silica gel (100% hexane) afforded 70 mg of the product (30% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[CH:23][CH2:24][CH2:25][N:26]([CH3:43])[C:27]([C@@H:29]([N:34](C)[C:35](=O)OC(C)(C)C)[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[Cl:44]CCl>>[ClH:44].[CH:19]1[C:15]2[CH:16]=[CH:17][C:18]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[CH:23][CH2:24][CH2:25][N:26]([CH3:43])[C:27](=[O:28])[C@@H:29]([NH:34][CH3:35])[CH2:30][CH:31]([CH3:33])[CH3:32])[C:14]=2[CH:22]=[CH:21][CH:20]=1
Reactant: ClCCl
Reactant: CC(C)C[C@@H](C(=O)N(C)CCC=C1c2ccccc2C=Cc2ccccc21)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)N(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid were added to 169 mg (0.35 mmol) of t-butyl (1S)-1-{[[3-(5H-dibenzo[a,d][7]annulen-5-ylidene)propyl] (methyl) amino]carbonyl}-3-methylbutyl(methyl)carbamate, and they were stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. 1 N aqueous sodium hydroxide solution was added thereto to make it basic. After extracting with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was dissolved in 5 ml of 1,4-dioxane. 4 N hydrochloric acid/1,4-dioxane solution was added to the obtained solution. The resultant mixture was concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[NH:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1>CO.[C].[Pd]>[ClH:1].[ClH:1].[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH2:19])=[NH:18])=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: N=C(N)c1ccc(C=Cc2ccc(CN)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)c1ccc(CCc2ccc(CN)cc2)cc1
Yield: 132.5 %

Procedure:
A solution of 30 mg of 4-[2-(4-aminomethylphenyl)ethenyl]benzamidine dihydrochloride in 30 ml of methanol was catalytically reduced with 20 mg of a 5% palladium-carbon as catalyst. The reaction mixture was filtered from spent catalyst and concentrated under reduced pressure. The residue was recrystallized from a methanolisopropanol-ether mixture to yield 20 mg of 4-[2-(4-aminomethylphenyl)ethyl]benzamidine dihydrochloride; m.p. ≥260° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:19])[C:8]1[CH:13]=[C:12]([NH:14][C:15]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]2)=[S:16])[C:11]([F:17])=[CH:10][C:9]=1[Cl:18])=[O:4]
Reactant: COC(=O)COC(=S)c1cc(N=C=S)c(F)cc1Cl
Reactant: C1CCNNC1
Solvent: Cc1ccccc1
Product: COC(=O)COC(=S)c1cc(NC(=S)N2CCCCN2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 4.8 g of the resulting 2-chloro-4-fluoro-5-isothiocyanatothiobenzoic acid (methoxycarbonylmethyl) ester in 50 ml of toluene is added dropwise, with stirring, at from 20° to 250° C. to a solution of 1.4 g of hexahydropyridazine in 20 ml of toluene. The batch is then stirred for a further 8 hours at room temperature and is then concentrated by evaporation in vacuo to yield 4.4 g of 2-chloro-4-fluoro-5-(1-hexahydropyridazinylthiocarbonylamino)-thiobenzoic acid (methoxycarbonylmethyl) ester in resinous form.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].C[C:6]1[CH:11]=[C:10]([N+]([O-])=O)[C:9](C)=[CH:8][N+:7]=1[O-:16].[OH-].[Na+]>C(O)(=O)C>[Br:4][C:1]1[C:11]([CH3:10])=[CH:6][N+:7]([O-:16])=[C:8]([CH3:9])[CH:2]=1
Reactant: CC(=O)Br
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c[n+]([O-])c(C)cc1Br
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of acetyl bromide (43.09 mL, 582.81 mmol) in acetic acid (70 mL) was added 2,5-dimethyl-4-nitro-1-oxido-pyridin-1-ium (which may be prepared as described in Description 135) (9.8 g, 58.28 mmol) dropwise over 5 mins. After addition, the mixture was stirred at 80° C. overnight. The reaction mixture was poured on to ice and the solution basified to pH 8 with cold 2M sodium hydroxide. The aqueous layer was extracted with DCM (3x). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to a pale yellow solid, 4-bromo-2,5-dimethyl-1-oxido-pyridin-1-ium (D136) (12.3 g);
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[CH2:14]([O:18][P:19]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[CH2:15][CH2:16][CH3:17]>>[CH2:22]([O:21][P:19]([O-:26])([O:18][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:24][CH3:25].[CH2:10]([P+:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:27][CH2:28][CH2:29][CH3:30])[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CP(CC(C)C)CC(C)C
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Product: CCCCOP(=O)([O-])OCCCC
Product: CCCC[P+](CC(C)C)(CC(C)C)CC(C)C
Yield: 68.4 %

Procedure:
Tri-iso-butylphosphine (206.5 g, 98%, 1.0 mole) was added dropwise over a period of 2 hours to a flask containing 271.8 g (98%, 1.0 mole) of tributylphosphate at 200° C. under nitrogen and stirring. When the addition was complete, the mixture was stirred at the same temperature for an additional 15 hours. The mixture was cooled down and moved to a rotary evaporator and dried under 160° C./5 mm Hg for 5 hours. The product (320.7 g, yield 68.5%) was pure judged from NMR and liquid at room temperature. 1H-NMR (CDCl3, 300.13 MHz, δ): 3.76 (q, 4H, 2×CH3CH2CH2—CH2O—), 2.19 (q, 6H, 3×CH3 (CH3)CH—CH2P+), 1.96 (m, 3H, 3×CH3 (CH3)CH—CH2P+), 1.96 (m, 2H, CH3CH2CH2—CH2P+), 1.44 (m, 8H, CH3—CH2CH2—CH2O—), 1.24 (m, 4H, CH3—CH2CH2—CH2P+), 1.01 (d, 18H, 3×CH3CH(CH3)—CH2P+), 0.84 (t, 3H, CH3—CH2CH2CH2P+), 0.77 (t, 6H, 2×CH3—CH2CH2CH2O—). 31P-NMR (CDCl3, 81.015 MHz, δ): 32.60 (P+), −0.61 [d, (RO)2—P(═O)—O−].