Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([CH2:36][O:37][Si](C(C)(C)C)(C)C)=[CH:29][C:28]=2[CH:45]([CH3:47])[CH3:46])=[O:25])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4].O>CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:28]([CH:45]([CH3:46])[CH3:47])=[CH:29][C:30]([CH2:36][OH:37])=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])=[O:25])[C:6]1=[O:48])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CO[Si](C)(C)C(C)(C)C)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Solvent: O
Solvent: CO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(CO)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Yield: 89 %

Procedure:
A solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-[2,6-diisopropyl-4-(tert-butyldimethylsilyloxymethyl)phenyl]urea (6.75 g, 10.1 mmol) in methanol containing 15% HCl (100 ml) is stirred at room temperature for 3 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water (once) and an aqueous sodium hydrogen carbonate solution (once). The solvent is concentrated under reduced pressure, and the residue is purified by silica gel chromatography to give the title compound (5.0 g, 8.99 mmol) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:24][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(N)CCOc1ccc(OC(C)(C)C(=O)OCC)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
A sample of 2-amino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (612 mg, 1.73 mmol) and benzaldehyde (220 mg, 2.08 mmol) was dissolved in 10 mL of methylene chloride followed by addition of sodium triacetoxyborohydride (550 mg, 2.60 mmol). After 4 hours of stirring at room temperature the reaction mixture was partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The pH of the mixture was then adjusted to ˜13 with 1.0 N NaOH and the layers separated. The aqueous later was extracted with additional methylene chloride (25 mL). The combined organic phases were dried over sodium chloride, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/hexanes) to yield 492 mg of product (64%) as an oil. HPLC RT1=2.78 min; 1H NMR (400 MHz, CDCl3) δ7.28-7.18 (m, 5H), 6.79-6.76 (m, 2H), 6.70-6.68 (m, 2 H), 4.22-4.12 (m, 4H), 4.08-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.83-3.80 (d, J=12.7 Hz, 1H), 3.65-3.62 (d, J=12.7 Hz, 1H), 3.49-3.47 (m, 1H), 2.17-2.09 (m, 1 H), 2.00-1.92 (m, 1H), 1.49 (s, 6H), 1.26-1.20 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:27])=O>CN(C=O)C>[Cl:27][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCN(C)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
After repetition of the previous reaction, a mixture of 6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-3,4-dihydroquinazolin-4-one (2.15 g), thionyl chloride (25 ml) and DMF (0.18 ml) was stirred and heated to reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped twice with toluene. The residue was taken up in water, basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (4 times). The combined extracts were washed in turn with water and brine and filtered through phase separating paper. The filtrate was evaporated under vacuum and the residue was purified by column chromatography on silica using a 100:8:1 mixture of methylene chloride, methanol and a concentrated aqueous ammonium hydroxide solution (0.88 g/ml) as eluent. The solid so obtained was triturated under acetone, filtered and dried to give 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (1.2 g); Mass Spectrum: M+H+ 351.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
85 mg (63%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.257 mmol), 1-(4-methoxyphenyl)piperazine (50 mg, 0.257 mmol), DIPEA (0.070 mL, 0.386 mmol) and NaBH(OAc)3 (163 mg, 0.771 mmol).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5].NC(N)=[S:20].O.[OH-].[Na+]>Cl.C(O)(=O)C>[SH:20][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1S
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 73.9 g (0.24 mol) of 2-bromo-4-(4-clorophenyl)nicotinic acid and 22.0 g (0.29 mol) of thiourea in 100 ml of 5% HCl and 150 ml of acetic acid was stirred at 100° C. for 2 hours. The mixture was poured into water and 400 ml of 50% sodium hydroxide was added to the resultant mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was then acidified with 20% HCl, and the crystal thus precipitated was filtrated out and washed with water. The washed crystal was then dried to obtain a crude crystal of 2-mercapto-4-(4-chlorophenyl)nicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14](F)[C:13]=1[N+:21]([O-:23])=[O:22])[CH3:11]>>[CH2:10]([C:12]1[C:13]([N+:21]([O-:23])=[O:22])=[C:14]([C:15]([F:19])=[C:16]([F:18])[CH:17]=1)[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1])[CH3:11]
Reactant: Nc1ccc(I)cc1F
Reactant: CCc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Product: CCc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Yield: 58.5 %

Procedure:
2-Fluoro-4-iodoaniline (2.05 g, 10 mmol) and 1-ethyl-3,4,5-trifluoro-2-nitrobenzene (2.37 g, 10 mmol) were reacted using the condition described in example 1 (Step A) to form the title compound (2.47 g, 60%); m/z=407 [M−1]
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:18]=[CH:17][C:6]([CH:7]2[N:20]3[N:19]=[CH:23][N:22]=[C:21]3[NH:24][C:14]([CH3:15])=[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ncnn2C1c1ccc(C#N)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (300 mg, 1.2 mmol) and 1H-1,2,4-triazole-3-amine (130 mg, 1.5 mmol, 1.2 eq.) were dissolved in DMF (3 ml) and solid sodium bicarbonate (518 mg, 6.2 mmol, 5 eq.) was added. The mixture was stirred at 65° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (233 mg, 50% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9]O)=[C:6]([Cl:8])[N:7]=1.S(Cl)([Cl:15])=O>>[NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([CH2:9][Cl:15])=[C:6]([Cl:8])[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1nc(CO)c(Cl)nc1N
Product: N#Cc1nc(CCl)c(Cl)nc1N

Procedure:
A suitable method of synthesizing 7-NR1R2 -MTX wherein either both R1 and R2 are hydrogen, or one is hydrogen and the other is C1 -C5 alkyl, is outlined in FIGS. 1A and 1B. A suitable method of synthesizing 7-NR1R2 -MTX wherein both R1 and R2 are hydrogen comprises (a) reacting phosphorus oxychloride with 3-amino-6-(chloromethyl)-2-pyrazinecarbonitrile 4-oxide (1) to yield 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile (2); (b) reacting 3-amino-5-chloro-6-(hydroxymethyl)-2-pyrazinecarbonitrile with thionyl chloride to form 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile (4); (c) reacting 3-amino-5-chloro-6-(chloromethyl)-2-pyrazinecarbonitrile with ethyl 4-methylaminobenzoate (3) to form ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate (5); (d) reacting ethyl 4-[N-(2-amino-3-cyano-6-chloro-5-pyrazinylmethyl)-N-methylamino]benzoate with guanidine to form 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate (6); (e) reacting 4-[N-(2,4-diamino-7-chloro-6-pteridinylmethyl)-N-methylamino]benzoate with ammonia to form 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (7a); and (f) coupling 4-[N-(2,4,7-triamino-6-pteridinylmethyl)-N-methylamino]benzoic acid and diethyl L-glutamate hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1>ClCCl.CO>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][N:8]1[CH2:7][CH2:6][O:5][C:4]1[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCc2ccccc2C1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCc2ccccc2C1

Procedure:
Prepared analogously to Example 3.1.b. from 1.4 g (2.77 mmol) of 2-[2-(2-methoxy-4-nitrophenoxy)ethyl]-1,2,3,4-tetrahydroisoquinoline (65%). Yield: 1.2 g (94% of theory); C18H22N2O2 (M=298.38); calc.: molecular ion peak (M+H)+: 299; found: molecular ion peak (M+H)+: 299; Rf value: 0.5 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NCCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:32])[N:11]([S:13]([C:16]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH:41]([OH:46])[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:40][CH:41]([OH:46])[C:42]([F:45])([F:44])[F:43])[C:10](=[O:32])[N:11]([S:13]([C:16]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:30])([F:29])[F:31])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)nn1S(=O)(=O)c1ncnn1Cc1ccccc1C(F)(F)F
Reactant: OC(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=c1n(S(=O)(=O)c2ncnn2Cc2ccccc2C(F)(F)F)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h

Procedure:
50 mg (0.10 mmol) of the compound from Example 95A together with 50 mg (0.16 mmol) of cesium carbonate were dissolved in 0.5 ml of DMF, and 30 mg (0.16 mmol) of 3-bromo-1,1,1-trifluoropropan-2-ol were added. The mixture was then stirred at 75° C. for 8 h. For work-up, the reaction mixture was diluted with 0.5 ml of acetonitrile and directly purified chromatographically [Method 19]. This gave 15 mg (22% of theory) of the target compound.
Reaction SMILES: N1C=CC=CC=1.[S:7](=[O:10])(=[O:9])=[O:8].[CH2:11]([OH:33])[C@H:12]1[O:17][C@H:16]([O:18][C@:19]2([CH2:28][OH:29])[O:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([OH:26])[C@@H:20]2[OH:27])[C@H:15]([OH:30])[C@@H:14]([OH:31])[C@@H:13]1[OH:32]>O>[CH2:11]([O:33][S:7]([OH:10])(=[O:9])=[O:8])[C@H:12]1[O:17][C@H:16]([O:18][C@:19]2([CH2:28][O:29][S:7]([OH:10])(=[O:9])=[O:8])[O:23][C@H:22]([CH2:24][O:25][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:21]([O:26][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:20]2[O:27][S:7]([OH:10])(=[O:9])=[O:8])[C@H:15]([O:30][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:14]([O:31][S:7]([OH:10])(=[O:9])=[O:8])[C@@H:13]1[O:32][S:7]([OH:10])(=[O:9])=[O:8]
Reactant: O=S(=O)=O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(O)OC[C@H]1O[C@@](COS(=O)(=O)O)(O[C@H]2O[C@H](COS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@H](OS(=O)(=O)O)[C@H]2OS(=O)(=O)O)[C@@H](OS(=O)(=O)O)[C@@H]1OS(=O)(=O)O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
254.7 g (1.6 mol) of sulfur trioxide pyridine were slurried in 1300 ml of water-free pyridine. With stirring, 68.5 g (0.2 mol) of sucrose were added. The reaction mixture was heated to 65° C. and kept at this temperature for 240 minutes. As the reaction proceeded, the substance was separated as a thick flowing oil. When the reaction was terminated, the agitator was stopped, the pyridine phase was decanted, and the oily phase was dissolved in 600 ml of ion-exchanged water.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C[CH2:13][N:14](CC)[CH2:15]C.CNC.O>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH3:15])[CH3:13])=[O:7]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 3-(chloromethyl)benzoyl chloride (426 μL, 3 mmol) and Et3N (626 μL, 4.5 mmol) in THF (5 mL) was treated with dimethylamine (1.5 mL, 2-M in THF, 3 mmol), stirred at room temperature for 1 h, poured into water, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo to give the title compound (580 mg, 98%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.46-7.34 (4H, m), 4.59 (2H, s), 3.11 (3H, s) and 2.98 (3H, s); Anal. Calcd for C12H12N6O2.0.2H2O: C, 49.38; H, 4.28, N, 28.79. Found: C, 49.25; H, 4.09; N, 28.47.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[CH:14][N:13]=1>O.CO>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[C:15]([CH3:19])=[CH:14][N:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cnc(Cl)nc1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1124.2 %

Procedure:
Sodium hydroxide (2.38 g, 5.9 mmol) was dissolved in water (10 mL), 4-aminothiophenol (6.77 g, 5 4 mmol) was added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for 30 minutes. 2,4-Dichloro-5-methylpyrimidine (7.05 g, 4 3 mmol) was slowly added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for a further 1 hour during which time a precipitate formed. This precipitate was isolated by filtration, washed with minimum ice cold diethyl ether and dried under vacuum to give 4-[(2-chloro-5-methylpyrimidin-4-yl)thio]aniline (8.49 g, 92%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[CH3:15])[CH3:2].C1C(=O)N([Br:23])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[N:5]=[C:4]1[CH2:15][Br:23])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCn1c(C)nc2c([N+](=O)[O-])cccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1c(CBr)nc2c([N+](=O)[O-])cccc21
Temperature: 90 °C
Yield: 54.3 %

Procedure:
To a solution of 0.216 g (1.05 mmol) 1-ethyl-2-methyl-4-nitrobenzimidazole, 50 mL carbon tetrachloride and 0.375 g (2.11 mmol) NBS, was added 50 mg of AIBN. The reaction mixture was heated to 90° C. for five hours and the solution was cooled to room temperature. The solution was concentrated under reduced pressure and the resulting oil was chromatographed on silica to yield 0.16 g (0.57 mmol, 54%) of a light yellow oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([O:20]C)[CH:11]=1>C(O)(=O)C.Br>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:11]=[C:12]([OH:20])[C:13]([OH:19])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: COc1cc(-c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1O
Agent: Br
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3[nH]2)cc(O)c1O

Procedure:
A suspension of 860.1 mg of 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 ml of glacial acetic acid and 10 ml of 48 percent hydrobromic acid is heated to boiling under reflux for 72 hours. The mixture is then evaporated and the residue is treated four times with 50 ml of toluene each time, which is again distilled each time. There is obtained 5-(2-benzimidazolyl)-3-nitropyrocatechol of m.p. >300° (from acetone/water).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[CH:35]([CH3:46])[CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42]
Reactant: CC(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CN(C)C(=O)OC(C)(C)C)c(F)c1
Yield: 36 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (380 mg, 1.16 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl(methyl)carbamate (400 mg, 1.1 mmol) to afford the desired product (190 mg, 36%) as a yellow solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[C:3]([C:5]1[S:18][C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.[NH2:26][C:27]([NH2:29])=[S:28]>CC(C)=O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:2]1[S:28][C:27]([NH2:29])=[N:26][C:3]=1[C:5]1[S:18][C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[O:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: O=C(c1cc2c(s1)-c1ccccc1OCC2)C(Br)c1ccccc1Cl
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Nc1nc(-c2cc3c(s2)-c2ccccc2OCC3)c(-c2ccccc2Cl)s1
Temperature: 25 °C

Procedure:
A solution of crude 2-bromo-2-(2-chlorophenyl)-1-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)ethanone (0.21 mmol) in 2 mL acetone was treated with thiourea (48 mg) and the resultant suspension was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and concentrated. The crude residue was purified by reverse phase HPLC to give 280 as a colorless solid. 1H NMR (400 MHz, DMSO-d6) δ 7.65 (m, 1H), 7.55-7.53 (m, 2H), 7.47-7.43 (m, 2H), 7.29 (br s, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.45 (s, 1H), 4.17 (t, 2H), 2.95 (t, 2H). MS: (ESI+) 411.1
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:24][CH3:25].C(N(CC)CC)C.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>C(Cl)Cl>[CH3:25][O:24][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:2]=1[NH:1][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])[C:6]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][N:11]2[CH:19]=[CH:20][CH:21]=[C:10]2[CH2:9]1)=[O:7]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 60 mg of triethylamine followed by a solution of 56 mg of n-butylsulfonyl chloride in 0.3 ml of methylene chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue which is dissolved in methyl alcohol, stirred for 1 hour and evaporated in vacuo to a residue which is treated with 2 ml of NH4Cl and extracted with 15 ml of ethyl acetate. The organic extract is washed with saturated NaHCO3, brine, dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated to a residue. The residue is stirred with ether-hexanes to give 0.14 g of light yellow solid. MS(CI): 454(M+H).