Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]C(=O)N(C)C)=[C:4]([Cl:15])[CH:3]=1.[OH-].[K+].Cl>C(O)C.O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([SH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: CN(C)C(=O)Sc1c(Cl)cc(N)cc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(S)c(Cl)c1
Temperature: 95 °C
Yield: 68.7 %

Procedure:
A solution of dimethyl-thiocarbamic acid S-(4-amino-2,6-dichloro-phenyl) ester (81) (2.0 g, 7.5 mmol) in ethanol was treated with a 3N aqueous potassium hydroxide solution. The reaction was heated to 95° C. for 2 d. At this time, the reaction was cooled to 25° C. and was then acidified to pH=2 with a 3N aqueous hydrochloric acid solution. This solution was diluted with water (500 mL) and then was extracted with ethyl acetate (2×250 mL). The organics were dried with magnesium sulfate, filtered, and concentrated under vacuumto an orange solid. The solid was slurried in chloroform, collected by filtration and washed with chloroform. The filtrate was concentrated under vacuum and purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 85:15 petroleum ether/ethyl acetate) to afford 4-amino-2,6-dichloro-benzenethiol (82) (1.0 g, 69%) as a white solid; EI(+)-HRMS m/e calcd for C6H5Cl2NS (M+) 192.9520, found 192.9519. Exact Mass=192.9520; Molecular weight=194.08
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:28])[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[NH2:31][CH2:32][CH2:33][CH2:34][OH:35]>CCCCCC.C(OCC)(=O)C>[OH:35][CH2:34][CH2:33][CH2:32][NH:31][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:28]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 33 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 3-amino-1-propanol, the title compound was synthesized in the same manner as in Example 143. Yield: 33%. Melting point: 185-186° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([N:8]=[C:9]([NH2:11])[NH2:10])#[N:7].[OH2:12]>>[S:2](=[O:4])(=[O:3])([OH:5])[NH2:1].[C:9]([NH:8][C:6]([NH2:7])=[O:12])(=[NH:11])[NH2:10]
Reactant: N#CN=C(N)N
Reactant: O
Agent: NS(=O)(=O)O
Product: N=C(N)NC(N)=O
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Sulfaminic acid (97 g) was added batchwise to a solution composed of 84 g dicyandiamide and 300 ml of water at 80° C. whereby the temperature was not permitted to exceed about 95° C. After addition was complete, the temperature was held at 95° C. for 20 minutes, after which the solution was evaporated using a water-jet vacuum. By this process 189 g (=95% of theoretical) guanylurea sulfamate was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1[Cl:14].S(Cl)(Cl)=O.O.N.[CH3:21]O>S(=O)(=O)(O)O>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13][CH3:21])=[O:12])[C:3]=1[Cl:14]
Reactant: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Reactant: CO
Agent: N
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nc(C2CC2)nc(N)c1Cl
Temperature: 5 °C

Procedure:
To a solution of 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (i.e. the product of Step D1 or D2 of Example 2) (2.0 g, 8.5 mmol) in methanol (20 mL) was added dropwise thionyl chloride (4 mL, 70 mmol). The mixture was heated at reflux for 24 h. Concentrated sulfuric acid (5 drops) was added, and the reaction mixture was heated at reflux for 16 h. After the mixture was cooled, water (30 mL) was added, and aqueous ammonia (28%, 10 mL) was added dropwise. The mixture was cooled to 5° C., and the solid was isolated by filtration, washed with water and dried in a vacuum oven at 40° C. to afford the title product (2.3 g), a compound of the present invention.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([CH3:8])[N:7]=1.ClC1C(C#N)=NC(C)=C(CC)N=1.Cl.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:9]([C:5]1[N:4]=[C:3]([C:11]#[N:12])[C:2]([N:28]2[CH2:27][CH2:26][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][CH2:29]2)=[N:7][C:6]=1[CH3:8])[CH3:10]
Reactant: CCc1nc(C#N)c(Cl)nc1C
Reactant: c1ccc2c(c1)CCNCC2
Agent: CCc1nc(Cl)c(C#N)nc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C#N)c(N2CCc3ccccc3CC2)nc1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
A solution of 0.300 g (1.65 mmol) of the 1:1 mixture of the 3-chloro-6-ethyl-5-methyl-pyrazine-2 -carbonitrile and the 3-chloro-5-ethyl-6-methyl-pyrazine-2-carbonitrile, of 0.395 g (1.30 mmol) of 2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and of 0.566 g (2.60 mmol) of N-ethyl-diisopropylamine in 1.0 ml of N,N-dimethylformamide was stirred at room temperature for 60 hours and then at 60° C. for 18 hours. The reaction mixture was subsequently poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of ethylacetate. The combined ethylacetate phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was then chromatographed on silica gel using dichloromethane as eluent giving 0.086 g (0.29 mmol, 18% of theory) of the 6-ethyl-5-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid after crystallization from dichlormethane/pentane; MS: 293 (M+H)+; and 0.074 g (0.25 mmol, 15% of theory) of the 5-ethyl-6-methyl-3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as yellowish solid; MS: 293 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Br)ccc1F
Product: O=c1cc(N2CCN(Cc3cc(Br)ccc3F)CC2)nc[nH]1

Procedure:
6-[4-(5-Bromo-2-fluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-fluorobenzaldehyde. Mass spectrum (ES) MH+=367.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:10][CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccccc1
Solvent: O
Product: COc1ccc(S(=O)(=O)O)cc1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of methoxybenzene. Then, while the stirring was continued, the temperature was raised into 80 to 85° C., reacting for 3 hours. After the reaction, distillation water was added, adjusting the concentration into 55%. Then, the temperature at about 40° C. was gradually cooled. Upon the temperature reached at 20° C., a small amount of a crystalline of p-methoxybenzenesulfonic acid (4-methoxybenzenesulfonic acid), which was provided in advance, was added, generating crystalline deposition of p-methoxybenzenesulfonic acid in the system. The crystalline as obtained was collected by filtering, into which water was added and the liquid temperature was again raised at 40° C. to dissolve. The concentration was adjusted to have 55%. Then, the temperature at about 40° C. was gradually cooled. Upon the temperature reached at 20° C., a small amount of a crystalline of p-methoxybenzenesulfonic acid, which was provided in advance, was added again, generating crystalline deposition of p-methoxybenzenesulfonic acid. The crystalline was collected by filtration so as to obtain methoxybenzenesulfonic acid in which the para compound was included at 98 mole % in the whole of methoxybenzenesulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].CN1CCCC1=[O:32]>C(O)(C)C.CO>[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[CH3:1][C:2]1[CH2:22][S:21][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:20])[C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:23]([OH:25])=[O:24].[OH2:32]
Reactant: CN1CCCC1=O
Agent: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccc(O)cc3)[C@H]2SC1
Solvent: CO
Solvent: CC(C)O
Product: O
Temperature: 10 °C

Procedure:
Cefadroxil 1-methyl-2-pyrrolidone solvate (30 g) was slurried in a mixture of 110 ml isopropyl alcohol and 40 ml of methanol kept at 45°-48° C. for 100'. After cooling to 10° C. the mixture was filtered, the product washed with acetone and dried at 40° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCNCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 195.1 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) and piperazine (7.3 ml) are added to the bottle within 20 min, the above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (12.4 g). The yield is about 72.7%.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:25])[CH2:23][CH3:24].CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:25][CH2:22][CH2:23][CH3:24])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCCN
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: ClCCl
Solvent: CO
Product: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 90 mg, 0.19 mmol) and propylamine (2.5 ml, 70% w/v in water). Yield 68.8 mg (0.15 mmol, 80%), mp 160–162÷C, Rƒ 0.20 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.99 (t, 1H, J=4.80 Hz, NH), 6.87 (s, 2H, NH2), 5.80 (d, 1H, J=8.24 Hz, H-1′), 5.67–5.63 (m, 1H, OH-2′), 5.30 (d, 1H, J=6.18 Hz, OH-5′), 5.18 (d, 1H, J=3.77 Hz, OH-3′), 4.56–4.51 (m, 1H, H-2′), 4.09–4.03 (m, 1H, H-3′), 3.96–3.94 (m, 1H, H-4′), 3.62–3.59 (m, 4H, H-5′, NHCH2), 1.57 (q, 2H, J=7.20 Hz, CH2CH3), 0.88 (t, 3H, J=7.50 Hz, CH3); MS m/z 451 (M+H)+; Anal. (C13H19IN6O4) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([O:34][C:35]([NH:37][S:38]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:40])=[O:39])=[O:36])[CH2:31][CH2:32][CH3:33].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:30]([O:34][C:35]([N:37]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[S:38]([NH:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(=[O:39])=[O:40])=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)NS(=O)(=O)NCC(=O)OCC
Reactant: COc1ccc(CO)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)N(Cc1ccc(OC)cc1)S(=O)(=O)NCC(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of (4-methoxyphenyl)-methanol (1.4 g, 8.5 mmol) and triphenyl-phosphane (2.6 g, 8.5 mol) in dry THF was added a solution of ethyl 2-((N-(butyloxycarbonyl)sulfamoyl)amino)acetate from the previous step (2.4 g, 8.5 mol) and DIAD (2.0 g, 8.5 mmol) in dry THF dropwise at 0° C. under N2 atmosphere. The mixture was stirred at 0° C. for 2 h, warmed to RT and stirred overnight. After the solvent was removed in vacuo, the residue was purified by column chromatography to afford ethyl 2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate (2.3 g, 69%) as a white solid. 1H-NMR (CDCl3): δ 7.32 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.71 (m, 1H), 4.76 (s, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.55 (d, J=5.2 Hz, 2H), 1.54 (s, 9H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH2:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:37]=[CH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([S:39]([NH:42][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])=[CH:35][CH:34]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=2)=[CH:33][CH:32]=1)(=[O:41])=[O:40])[CH:37]=[CH2:38]
Reactant: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: C=CCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 84.4 %

Procedure:
4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (44 mg, 0.090 mmol), prop-2-ene-1-sulfonamide (13.07 mg, 0.108 mmol), HATU (51.3 mg, 0.135 mmol), and Hunig's Base (0.079 mL, 0.449 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give N-(allylsulfonyl)-4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (45 mg).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH2:8][CH2:7][NH:6][CH:5]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.Br[CH:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25]([NH:27][CH3:28])=[O:26].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:28][NH:27][C:25](=[O:26])[CH:24]([N:6]1[CH2:7][CH2:8][C:9]2[S:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CNC(=O)C(Br)c1ccccc1
Reactant: Cc1cc2c(s1)CCNC2CCc1ccc(C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(c1ccccc1)N1CCc2sc(C)cc2C1CCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 10.6 %

Procedure:
To a solution of 300 mg (0.92 mmol) 2-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine in 13 mL acetonitrile was added 210.3 mg (0.92 mmol) 2-Bromo-N-methyl-2-phenyl-acetamide (commercially available), 473 uL (2.76 mmol) N-ethyldiisopropylamine and 138 mg (0.92 mmol) sodium iodide. The solution was stirred for 18 h at 60° C. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with water and Na2CO3 aq. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The diastereoisomeric product eluting first (obtained after evaporation from the product containing fractions) was dissolved in methanol, treated with Norit, heated to reflux, filtered and evaporated to dryness to yield 46 mg (11%) of N-methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl}-2-phenyl-acetamide (diastereoisomer 1) (MS(m/e): 472.9 (MH+)) as light yellow oil.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=3)[N:6]2[CH:30]=1)=O.[N+](=[C:33](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:28][CH:29]=3)[N:6]2[CH:30]=1)#[CH:33]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cn2c(-c3ccc(C(=O)OC(C)(C)C)cc3)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of compound 81a (239 mg, 0.580 mmol) in anhydrous THF (8 mL) and anhydrous MeOH (3 mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (164 mg, 0.850 mmol) in MeOH (2 mL) was added followed by potassium carbonate (252 mg, 1.82 mmol). The resulting yellow suspension was stirred at rt for 18 h. The mixture was filtered through a pad of diatomaceous earth. The filter cake was washed CH2Cl2. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM and washed with diluted NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on preparative TLC (EtOAc/CH2Cl2; 2:3, v/v) to afford compound 81b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H25N4O3: 405.2 (M+H). found: 405.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=S)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][N:24]=[CH:23]1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12]4[C:13](=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]2=[N:30][CH2:29][CH2:28][CH2:27][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:14]=[CH:15][CH:16]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CN2C(=S)c3cccc4cccc2c34)cc1
Reactant: NCCCn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.5 g of 1-[(4-methylphenyl)methyl]benz[cd]indole-2(1H)-thione (Ca) and 1.2 g of 1H-imidazole-1-propanamine in 200 ml of ethyl alcohol is stirred and heated. A 2.7 g portion of mercuric acetate is added, the mixture is stirred at reflux for 6 hours, cooled to room temperature and treated with 2N sodium hydroxide (pH 9). After filtering the solution through diatomaceous earth, the reaction is concentrated in vacuo. The resulting oil is dissolved in dichloromethane, washed neutral with water, dried over sodium sulfate and concentrated in vacuo. The crystalline residue is recrystallized from dichloromethane/hexane giving 2.2 g of the desired product, mp. 94°-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH2:38](Br)[CH2:39][CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH2:38][CH2:39][CH3:40])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: CCCBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: CCCOc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with propyl bromide
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 76.2 %

Procedure:
Following general procedure M, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (96 mg, 0.33 mmol) to afford the desired product (113 mg, 76%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 9.01 (s, 1H), 8.09-7.88 (m, 3H), 7.36 (s, 2H), 7.33-7.28 (m, 2H), 7.17-7.08 (m, 2H), 3.47 (s, 2H), 3.08 (q, J=7.1 Hz, 2H), 2.16 (s, 6H), 0.98 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[C:20]([O:21][CH2:22][C@@H:23]([N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16])(=[O:3])[CH3:2].[CH3:39][Mg]Br>C1COCC1>[OH:3][C:1]([C:4]1[C:20]([O:21][CH2:22][C@@H:23]([N:28]2[C:29](=[O:38])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]2=[O:37])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:19][C:7]2[N:8]([CH3:18])[C:9](=[O:17])[C:10]3[C:15]([C:6]=2[CH:5]=1)=[CH:14][CH:13]=[N:12][C:11]=3[CH3:16])([CH3:39])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc2c3ccnc(C)c3c(=O)n(C)c2cc1OC[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Solvent: C1CCOC1
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(C)(C)O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of (S)-2-(1-((9-acetyl-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (220 mg, 0.430 mmol) in THF (6 mL) was added methyl magnesium bromide (1.4 M in diethyl ether) (0.922 mL, 1.290 mmol) at −10° C. and stirred for overnight at RT. The reaction mixture was carefully quenched with water and diluted with EtOAc. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford (S)-2-(1-((9-(2-hydroxypropan-2-yl)-4,6-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.2 g, 0.152 mmol, 35% yield) as a brown gummy solid. LC/MS (ESI) m/e 528.2 [(M+H)+, calcd for C31H34N3O5 528.2; LC/MS retention time (method D): tR=0.89 min.