Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[O:7][CH3:6]
Reactant: COC(=O)Cl
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 52 parts of 2-methylpseudourea hydrogen sulfate in 250 parts of water at 0°-5° C. is added 31 parts of methyl chloroformate followed by dropwise addition of 74 parts of 50% sodium hydroxide. The reaction mass is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated. The residue is triturated with hexane to give 23 parts of methyl N-(1-amino-1-methoxy methylene)carbamate melting at 36°-39.5° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[C:5]([CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18](O)(=[O:20])C.C1N2CN3CN(C2)CN1C3.O>C1(C)C=CC=CC=1>[CH:18]([C:3]1[C:4]([CH3:17])=[C:5]([CH3:16])[C:6]2[C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:13])[C:11]=2[C:2]=1[OH:1])=[O:20]
Reactant: Cc1cc(O)c2c(c1C)C(C)(C)CCC2(C)C
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C)c2c(c(O)c1C=O)C(C)(C)CCC2(C)C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Formylation. 1-Hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (15 g, 0.0646 mol) was stirred with glacial acetic acid (100 mL), and hexamethylenetetramine (15 g, 0.107 mol) was added in one portion. The mixture was heated at 100° C. for 2 h. Hot water (100 mL) was added and the heating continued for an additional 0.5 h at 100° C. The mixture was cooled to 20° C., toluene (25 mL) was added, and the mixture was stirred vigorously. The organic layer was separated, washed with water (2×10 mL), then neutralized with 5% NaHCO3 solution and finally washed with brine (10 mL). The solvent was removed by distillation, and the residue crystallized from hexane, to give 2-formyl-1-hydroxy-3,4,5,5,8,8-hexamethyl-5,6,7,8-tetrahydronaphthalene (8.8 g), GLC purity 94%. 1H-NMR (CDCl3) δ12.94 (1H, s), 10.36 (1H, s), 2.43 (3H, s), 2.36 (3H, s), 1.65 (4H, s), 1.48 (6H, s), 1.46 (6H, s). 13C-NMR (CDCl3) δ195.4 (1C, d), 161.4 (1C, s), 156.0 (1C, s), 138.0 (1C, s), 131.9 (1C, s), 126.6 (1C, s), 116.7 (1C, s), 40.2 (1C, t), 37.9 (1C, t), 36.5 (1C, s), 35.1 (1C, s), 29.5 (2C, q), 28.1 (2C, q), 19.3 (1C, q), 14.1 (1C, q). IR (KBr) 1628 cm-1, MS (m/e) 260.3 (M+, 38.6), 245.2 (100.0), 175.1 (28.7), 189.1 (20.1).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: O=C1CNC(=O)N1
Reactant: Oc1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 40 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4.0 g (40 mmol) of hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction system was then allowed to cool to room temperature. To the reaction system was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.0 g (yield: 52%) of 5-(p-hydroxyphenyl)hydantoin.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:15]([O:17]CC)=[O:16])=[C:4]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]12.[OH-].[Na+].Cl>>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C:3]([C:15]([OH:17])=[O:16])=[C:4]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:5]12
Reactant: CCOC(=O)c1c2n(c3ccccc13)CCCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c2n(c3ccccc13)CCCCC2

Procedure:
The title compound (D5) was prepared from ethyl 7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-11-carboxylate by hydrolysis with sodium hydroxide as in the method of Description 3d. After 4 hours heating under reflux, the mixture was acidified with 5M HCl acid and the white solid formed filtered off and dried (82%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[CH2:6]2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([Mg]Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>CCOCC>[F:12][C:13]([F:26])([F:27])[C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH3:11])[CH2:6]3)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: CC1=Cc2c(Br)cccc2C1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Solvent: CCOCC
Product: CC1=Cc2c(cccc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1

Procedure:
4-Bromo-2-methylindene (10.7 g, 51 mmol) and NiCl2(Ph3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-bis(trifluoromethyl)phenylmagnesium bromide (51 mmol) as a Et2O solution was added under vigorous stirring and the reaction stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 2.2 g (13%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1([N:12]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10]1>C(#N)C>[Cl:1][C:26]1[CH:25]=[C:24]([O:27][CH3:28])[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][C:21]=1[CH2:20][N:12]([CH:9]1[CH2:11][CH2:10]1)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)ccc1OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c(Cl)cc1OC
Temperature: 75 °C
Reaction time: 5 h
Yield: 80.7 %

Procedure:
N-Chlorosuccinimide (110 mg) was added to a solution of tert-butyl cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]carbamate (300 mg) in acetonitrile (5.0 ml) under ice cooling and the mixture was stirred at room temperature for an hour and at 75° C. for 5 hours. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a NH-silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/1 to 3/1) to give tert-butyl [2-chloro-4-methoxy-5-(3-methoxypropoxy)benzyl]cyclopropylcarbamate (265 mg) as a colorless oil.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([NH:25][C:26]3C=CC=CC=3O)=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CNC.O1CCCC1>ClCCl>[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C@@H:22]([N:33]3[C@H:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:37](=[O:43])[NH:36][C@H:35]([CH:44]4[CH2:52][C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[CH2:45]4)[C:34]3=[O:53])[C:23]([N:25]([CH3:26])[CH3:1])=[O:24])=[CH:21][C:16]=2[CH:15]=[CH:14]1
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc2sccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
Carbonyldiimidazole (100 mg) was suspended in anhydrous dichloromethane (1 mL) and the suspension was left at room temperature for 15 minutes. 2RS)-2-(1-benzothien-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (200 mg) was then added and the mixture was stirred at room temperature for 5 hours 20 minutes. The resulting brown solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (1.0 mL, 6 equiv.) and the resulting mixture was stirred for 30 minutes and then left to stand at room temperature for 18 hours 15 minutes. The reaction mixture was evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 1:1 v/v ethyl acetate:cyclohexane. The required fractions were combined and evaporated in vacuo to give (2R)-2-(benzothien-5-yl) -2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide as a white solid (90 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CN(C)C(=O)Cl
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), N,N-dimethylcarbamoyl chloride (3.60 uL, 0.0392 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.93 (s, 6H), 4.13-4.18 (m, 2H), 7.39-7.45 (m, 1H), 7.51 (td, J=7.7, 1.3 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.14 (s, 1H). MS (ES+): m/z=352.11 (100) [MH+]. HPLC: tR=3.11 min (ZQ3, polar—5 min).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)ccc1N1CCCCC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
Piperidine (320 μl, 3.23 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1,4-difluoro-2-nitrobenzene (225 mg, 1.41 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, 1-(4-fluoro-2-nitrophenyl)piperidine (298 mg, 94.2%) was yielded as an orange-colored oily material.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.Cl>O1CCOCC1>[NH:37]1[CH:36]=[C:35]([C:23]2[CH:22]=[CH:21][C:20]([C:11]3([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:25][CH:24]=2)[CH:39]=[N:38]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccn1

Procedure:
4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, followed by treatment with 4M HCl in dioxane, to obtain the title compound. LCMS (PS-B4) Rt 4.28 min [M+H]+ 305. 1H NMR (Me-d3-OD) δ 2.76 (2H, br.t), 3.01 (2H, br.d), 3.24 (2H, br.t), 3.39 (2H, br.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d).
Reaction SMILES: CC1C=CC(CO[N:8]=[C:9]([C:11]2[N:12]=[CH:13][N:14]([C@@H:17]3[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]3[OH:19])[C:15]=2[NH2:16])[NH2:10])=CC=1.[C:28](=S)=[S:29]>[OH-].[Na+].CO.N>[CH:13]1[N:14]([C@@H:17]2[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]2[OH:19])[C:15]2[C:11](=[C:9]([NH2:10])[NH:8][C:28]([N:16]=2)=[S:29])[N:12]=1
Reactant: S=C=S
Reactant: Cc1ccc(CON=C(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2N)cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 72 %

Procedure:
0.45 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide O-(p-methylbenzyl)-oxime was dissolved in a mixture of 0.30g of sodium hydroxide, 5 ml of methanol and 0.5 ml of carbon disulfide, and the resulting mixture was allowed to react in an autoclave at 130° C for 4 hours under autogenous pressure (about 10 Kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in water. The resulting aqueous solution was adjusted to a pH of 2 with hydrochloric acid, and the precipitated crystals were filtered to obtain crude 2-thioadenosine. The crude product was dissolved in aqueous ammonia, filtered and adjusted to a pH of 2 with hydrochloric acid to obtain 0.27 g of pure 2-thioadenosine having a melting point of 198° C (with decomposition) in a 72% yield.
Reaction SMILES: [CH2:1]([N:3]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])C.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:3]([C:11]([CH2:15][CH3:16])([CH3:14])[CH:12]=[O:13])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)CO
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)(C=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of tert-butyl ethyl(1-hydroxy-2-methylpropan-2-yl)carbamate (2.18 g, 10 mmol, 1.0 equiv) in DCM (150 mL) was added Dess-martin periodinane (4.24 g, 10 mmol, 1.0 equiv) portionwise at 0° C. The resulting mixture was stirred for 4 h at room temperature. Saturated solutions of aqueous sodium hydrogencarbonate and sodium thiosulfate were added. The resulting mixture was stirred for 0.5 h. The organic phase was separated, washed with saturated sodium hydrogencarbonate, brine, dried over sodium sulfate and concentrated to give 1.5 g (71%) of tert-butyl methyl(2-ethyl-1-oxopropan-2-yl)carbamate as a colorless oil.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C1(C)C=CC=CC=1.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21]C=C(Br)[N:18]=1>O>[Br:16][C:17]1[N:18]=[C:1]([O:3][CH2:4][CH2:5][OH:6])[CH:2]=[CH:21][CH:22]=1
Reactant: C=COCCO
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: OCCOc1cccc(Br)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
8.81 g of ethylene glycol monovinyl ether was added to toluene (100 mL) suspension of 2.4 g of sodium hydride (55% to 72%), and 9.48 g of 2,6-dibromopyridine was added thereto and stirred overnight at 110° C. The reaction liquid was left cooled to room temperature, and water was added thereto to separate the organic layer. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. 100 mL of methanol and 576 mg of p-toluenesulfonic acid hydrate were added to the resulting residue, and stirred for 5 hours. After this was concentrated under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to it, and extracted with ethyl acetate. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/1) to obtain 7.74 g of the entitled compound as a colorless oily substance.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.Cl.[NH2:18][C:19]1[N:24]=[C:23]([NH2:25])[C:22]([N:26]=O)=[C:21]([NH2:28])[N:20]=1>C(OCCO)C>[NH2:18][C:19]1[N:24]=[C:23]([NH2:25])[C:22]2[C:21](=[N:28][C:14]([NH2:15])=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][N:3]([CH3:16])[CH3:2])=[CH:12][CH:11]=3)[N:26]=2)[N:20]=1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Reactant: CN(C)CCOc1ccc(CC#N)cc1
Agent: Cl
Agent: [Na]
Solvent: CCOCCO
Product: CN(C)CCOc1ccc(-c2nc3c(N)nc(N)nc3nc2N)cc1

Procedure:
0.03 mol of metallic sodium is dissolved with stirring in 150 ml of 2-ethoxyethanol. 3.1 g (0.013 mol) of 4-(β-dimethylamino-ethoxy)-phenyl acetonitrile in the form of the hydrochloride are added with stirring followed by 1.45 g (0.01 mol) of 2,4,6-triamino-5-nitroso-pyrimidine. After stirring for 48 hours at 60°-65° C. excluding access of moisture, the mixture is centrifuged when still hot. Petroleum ether is added to the solution obtained until it becomes cloudy. The solution is kept refrigerated to complete precipitation. The precipitate is filtered off. It can be recrystallized from n-butanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH3:22])[CH:20]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(C)c1
Reaction time: 17.5 h
Yield: 103.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.44 g, 7.45 mmol) was added to a suspension of 5-chloro-1H-indole-2-carboxylic acid ethyl ester (2.00 g, 8.94 mmol) in N,N′-dimethylformamide (DMF) (20 ml) under nitrogen. The mixture was stirred for 1 h before addition of the 3-methylbenzyl bromide (2.07 g, 2.48 ml) and the reaction stirred for 17.5 h. Water was added to reaction mixture which precipitated product as a gummy solid. Supernatant liquid was decanted and the solid washed with water. The product was dissolved in dichloromethane (DCM), washed with water, dried over magnesium sulfate and concentrated. Purification by silica chromatography using DCM as eluent, yielded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid ethyl ester (3.03 g, 95%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8](O)=[O:9])[S:6][CH:7]=1.C1N=C[N:15](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[O:9])[S:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 4-trifluoromethyl-thiazole-2-carboxylic acid (50 g, 1 eq.) in anhydrous THF (480 mL) was added carbodiimidazole (45.2 g, 1.1 eq.) portionwise under nitrogen in an ice/water bath (about 5° C.). The reaction mixture was stirred at room temperature for 16 hrs. NH4OH (25% in H2O; 1.930 mL) was added. The solution was stirred for 4 hrs, and then partitioned in DCM (500 mL) and H2O (500 mL). Aqueous layer was further extracted with DCM (500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to yield compound 285a as an orange solid in 72% yield. MS (ESI, EI+) m/z=197 (MH+).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:31])[NH:6][C:7]1[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=2)[N:10]=[C:9]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:8]=1.C(C1C=C(NC([NH:54][C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C@H:58]([O:65][C:66]3[CH:67]=[CH:68][C:69]4[N:70]([C:72]([N:75]5[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]5)=[N:73][N:74]=4)[CH:71]=3)[CH2:57][CH2:56]2)=O)N(C2C=CC(CO)=CC=2)N=1)(C)(C)C>>[C:27]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:54][C@@H:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[C@H:58]([O:65][C:66]3[CH:67]=[CH:68][C:69]4[N:70]([C:72]([N:75]5[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80]5)=[N:73][N:74]=4)[CH:71]=3)[CH2:57][CH2:56]2)=[O:31])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=2)[N:10]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(CO)cc2)n1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2cnn(CCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 3c and Intermediate 113c using analogous procedures to those described in Intermediate 106a. LCMS (Method 4): Rt 3.34 min, m/z 737 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH3:11]>>[Cl:8][C:7]1[C:2]([N:10]([CH3:11])[CH3:9])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CNC
Product: CN(C)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
74 g of 2,3-dichloro-pyrazine are added dropwise over the course of 15 minutes, whilst stirring, to 350 ml of a 40% strength aqueous solution of dimethylamine. Whilst doing so, the reaction temperature is kept at 30° C. by cooling. When the exothermic reaction has subsided the mixture is stirred for a further 15 hours at room temperature. The reaction mixture is then extracted by shaking with ether. The ether extracts are washed with water until neutral, dried over sodium sulphate and evaporated in a waterpump vacuum. The residue is distilled in a waterpump vacuum. 2-Chloro-3-dimethylamino-pyrazine, boiling point 100°-102° C./10 mm Hg, is thus obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>O.C(O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]([C:10]2[S:4][C:3]([NH2:5])=[N:2][N:1]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Fe](Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1nnc(-c2cccc(Br)c2)s1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
To a solution of thiosemicarbazide (0.493 g, 5.40 mmol, 1.0 equiv) in 6 mL of water at 70° C. is added a solution of 3-bromobenzaldehyde (0.633 ml, 5.40 mmol, 1.0 equiv) in 4.5 mL ethanol. After the precipitate is formed, iron(III) chloride hexahydrate (2.92 g, 10.81 mmol, 2.0 equiv) in 6 mL water is added and the mixture is stirred for 2.5 h at 85° C. Upon completion, the mixture is allowed to cool to room temperature and the resulting precipitate is collected by filtration and taken up in 12 mL pyridine. Ice water is then added to the pyridine slurry. The mixture is cooled then filtered to give 5-(3-bromophenyl)-1,3,4-thiadiazol-2-amine (553 mg, 39.9% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85-7.88 (m, 1H), 7.67 (d, J=8.22 Hz, 1H), 7.53-7.59 (m, 1H), 7.45 (s, 2H), 7.36 (t, J=8.02 Hz, 1H);
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:5][CH2:4]1.[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>>[NH2:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:1][CH2:2][CH:3]2[CH2:4][CH2:5][N:6]([C:9](=[O:12])[CH2:10][CH3:11])[CH2:7][CH2:8]2)[C:15]=1[C:16]#[N:17]
Reactant: CCC(=O)N1CCC(CO)CC1
Reactant: N#Cc1c(N)cccc1F
Product: CCC(=O)N1CCC(COc2cccc(N)c2C#N)CC1

Procedure:
Prepared as in Example 22a from 1-(4-(hydroxymethyl)piperidin-1-yl)propan-1-one (Example 153c) and 2-amino-6-fluorobenzonitrile as a pale-yellow solid (15%). MS 288 (MH+).