Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C2C(=CC(OC)=C(OC)C=2)N=C[N:3]=1.[CH3:16][O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N+:29]([O-:31])=[O:30])[CH:19]=1.S(Cl)(Cl)=O.N>>[CH3:16][O:17][C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:21]([C:22]([NH2:3])=[O:23])=[C:20]([N+:29]([O-:31])=[O:30])[CH:19]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: N
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
The common synthetic intermediate 4-chloro-6,7-dimethoxyquinazoline 5 used for synthesizing all the tested compounds by following literature procedures (Scheme 1). 4,5-dimethoxy-2-nitrobenzoic acid 1 was treated with thionyl chloride, and then reacted with ammonia to give 4,5-dimethoxy-2-nitrobenzamide 2 (Nomoto et al., 1990, Chem. Pharm. Bull 38: 1591-1595). The nitro group in compound 2 was reduced with sodium borohydride in the presence of copper sulfate (31) to give 4,5-dimethoxy- 2-aminobenzamide 3, which was cyclized by refluxing with formic acid to give 6,7-dimethoxyquinazoline-4(3H)-one 4. The quinazolinone 4 was refluxed with phosphorus oxytrichloride to provide the key starting material 5 with good yield.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23](O)=[O:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23]([NH:1][C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)=[O:24])=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
Ethyl 2-aminothiazole-5-carboxylate (2.21 g, 12.8 mmol) was condensed with 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 1.00 g, 3.2 mmol), using the procedure described for EXAMPLE 65, to give ethyl 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylate: m/z (ES+)=508.3 [M+MeCN+H]+. LiOH.H2O (410 mg, 9.8 mmol) was added to a solution of this ester (1.44 g, 3.1 mmol) in THF—H2O (3:1, 30 mL). The mixture was stirred at 20° C. for 16 h and then at 55° C. for 24 h. The solvents were removed in vacuo, then the residue was dissolved in H2O (50 mL). The aqueous solution was washed with EtOAc (20 mL), before being acidified to pH 1 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give a solid that was recrystallised (EtOAc-MeOH) to give the title compound: RTA=2.95 min; m/z (ES+)=480.2 [M+MeCN+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=O)=O.[C:22]([NH2:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>C(OCC)(=O)C>[C:5]1([NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1cccc2ccccc12)c1ccccc1
Yield: 94.6 %

Procedure:
Following the general procedure, 1-naphthyl tosylate (149 mg, 0.5 mmol) was coupled with benzamide (90 mg, 0.75 mmol) with the reaction time of 20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 117 mg (95%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([O:28]C)=[O:27])[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([OH:28])=[O:27])[CH:20]=2)=[O:18])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: COC(=O)c1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)cc(C(=O)O)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a stirred solution of methyl 4-((1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)carbamoyl)-6-methylpicolinate (160 mg, 0.37 mmol, Step-1, single enantiomer) in THF (5 mL) is added 2M aqueous sodium hydroxide (0.74 mL) at room temperature. The mixture is stirred at 50° C. overnight. After cooled to room temperature, the mixture is neutralized with 2M hydrochloric acid (0.74 mL) and extracted with ethyl acetate (5 mL×5). Combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 86 mg (56% yield) of the title compound as a yellow amorphous solid.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCO3)c2cc3c(cc21)OCO3
Yield: 41 %

Procedure:
The title compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)phenyl]urea and piperonal by the procedure described in example 10 in 41% yield, mp: 87-89° C. 1H NMR (CDCl3,): 6.77 (s, 3H), 6.68 (s, 1H), 6.28 (s, 1H), 5.96 (s, 2H), 5.92-5.90 (m, 2H), 5.22 (d, J=1.8, 1H), 4.98 (br s, 1H), 4.44 (m, 2H), 1.58-1.54 (m, 6H).
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[C:14]([O:17][CH2:18][C:19]1[CH2:26][S:25][CH:24]2[N:21]([C:22](=[O:28])[CH:23]2[NH2:27])[C:20]=1[C:29]([OH:31])=[O:30])(=[O:16])[CH3:15].C(=O)(O)[O-].[Na+]>CCOCC.O>[C:14]([O:17][CH2:18][C:19]1[CH2:26][S:25][CH:24]2[N:21]([C:22](=[O:28])[CH:23]2[NH:27][C:6](=[O:7])[CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:20]=1[C:29]([OH:31])=[O:30])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: O=C(Cl)C(n1cccc1)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(n3cccc3)S(=O)(=O)O)C2SC1

Procedure:
A solution of 2-sulfo-2-(1-pyrryl)acetyl chloride (1 equivalent) in ether is added to 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (1 equivalent) and sodium bicarbonate (about 3 equivalents) in water at about 0° C. After about 30 minutes the phases are separated, the pH adjusted to about 6.5 and the aqueous phase extracted with ethyl acetate. The ethyl acetate is dried over megnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].C(O)(=[O:23])C.OO.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[C:1]([C:5]1[C:6](=[O:20])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:23])=[CH:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: CC(=O)O
Agent: OO
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(=O)C1=C(O)CC(c2ccc(S(C)=O)cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 51.6 g (0.178 mol) of 2-propionyl-3-hydroxy-5-(4-(methylthio)phenyl)cyclohex-2-en-1-one (prepared as in U.S. Pat. No. 4,555,263) in 150 mL of methylene chloride and 150 mL of glacial acetic acid was added 20.15 g (0.178 mol) of 30 percent hydrogen peroxide dropwise over twenty minutes. The reaction temperature rose from 20° to 28° C. at which point, the reaction mixture was placed in a cold water bath. After 20 minutes, an additional 6.75 g (0.0595 mol) of 30 percent hydrogen peroxide was added dropwise and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with 150 mL of methylene chloride, washed thrice with 250 mL portions of water and then with 200 mL of aqueous sodium bicarbonate. The organic layer was separated and dried over Na2SO4 and the solvent removed in vacuo leaving 51.6 g (94.8 percent of theoretical) of the above named product melting at 111°-117° C. Recrystallization of the residue from 2-propanol gave the pure product in a yield of 46.1 g (84.7 percent of theoretical). The product melted at 116°-117° C.; Rf -0.07 (silica gel, 50:50 ethyl acetate-hexane and 1.0 percent acetic acid), 1H NMR (CDCl3): δ 1.1 (t, 3H, --CH2CH3), 2.70 (s, 3H, CH3SO--), 2.7-3.7 (m, 7H, ring protons and --CH2CH3), 7.25-7.70 (m, 4H, ArH), 18.1 (s, 1H, OH).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[CH3:16])=O.[C:25]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([C:7]2[C:6]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:5][S:4][C:3]=2/[CH:1]=[CH:30]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:9]([CH3:16])[CH:10]=1)#[N:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(-c2csc(C=O)c2-c2ccc(C#N)cc2C)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1scc(-c2ccc(OC)cc2)c1-c1ccc(C#N)cc1C
Temperature: 100 °C
Yield: 139.4 %

Procedure:
The mixture of compound 4-(2-formyl-4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 4A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.16 g, 0.48 mmol) and (carbethoxymethylene)triphenylphosphorane (Ph3P═CHCOOEt) (0.17 g, 0.48 mmol) in toluene (15 mL) was heated to 100° C. for 14 h. After being cooled down to room temperature, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1) to afford (E)-ethyl 3-(3-(4-cyano-2-methylphenyl)-4-(4-methoxyphenyl)thiophen-2-yl)acrylate (Scheme I, 5A, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (0.27 g, yield 100%) as a white solid.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[Li]C(C)(C)C.I[C:16]1[C:24]2[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=2)[N:18]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:17]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:3]([C:21]2[CH:20]=[C:19]3[C:24]([CH:16]=[N:17][N:18]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=2)=[CH2:4])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC1(Br)C=CC=CC1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccc2cnn(COCC[Si](C)(C)C)c2c1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 94.4 %

Procedure:
1-Bromostyrene (26 μL, 0.20 mmol, 2.0 equiv) was dissolved in THF (0.75 mL), cooled to −78° C. and was treated with t-BuLi (235 μL, 0.40 mmol, 1.70 M, 4.0 equiv). The mixture was allowed to warm to −42° C. for 10 min and was added to freshly dried zinc chloride (34 mg, 0.25 mmol, 2.5 equiv). The resulting solution was allowed to warm to 23° C. with stirring for 25 min. This mix was added to a mixture of neat 3,6-Diiodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (50 mg, 0.10 mmol, 1 equiv) and Pd(PPh3)4 (5 mg, 0.004 mmol, 0.04 equiv). After 10 min the reaction was determined to be complete by TLC monitoring and was quenched with saturated sodium bicarbonate. Organic material was extracted into ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (5:95 ethyl acetate-hexane) provided 3-Iodo-&6-(1-phenyl-vinyl)-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (33.1 mg, 70%): Rf sm 0.39, p 0.36 (ethyl acetate-hexane 1:9); 1H NMR (300 MHz, CDCl3) δ 7.50 (s, 1H), 7.42 (d, 1H, J=8.4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, J=1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J=1.0 Hz), 5.57 (d, 1H, J=1.0 Hz), 3.58 (t, 2H, J=8.2 Hz), 0.88 (t, 2H, J=8.2 Hz), −0.09 (s, 9H); HRMS (FAB) [m+H]/z Calc'd 477.0859, found 477.0866.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:14]=1[N+:22]([O-])=O)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:22]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cccc(N)c1-c1c(N)cccc1N

Procedure:
hydrogenating the 2,2′,6,6′-tetranitrobiphenyl with Pd/C, to obtain a 2,2′,6,6′-tetraminobiphenyl;
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([NH:11][C:12](=[NH:33])[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:22]1)=[O:20])[NH2:18])([O-:10])=[O:9].C(N(CC)CC)C.[CH3:41][C:42]([C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1)([CH3:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)Cl>[CH3:49][C:42]([C:50]1[CH:51]=[C:52]([S:56]([NH:18][C@H:17]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][CH2:22]2)=[O:20])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:33])[NH:11][N+:8]([O-:10])=[O:9])(=[O:57])=[O:58])[CH:53]=[CH:54][CH:55]=1)([CH3:41])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CC1CCN(C(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCN(C(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NS(=O)(=O)c2cccc(C(C)(C)c3ccccc3)c2)CC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The above 1-((S)-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine trifluoroacetate (2.1 g) is suspended in dry CH2Cl2 (50 ml) and stirred at 0° to 5° C. during the addition of triethylamine (1.3 g) to give a solution. To this solution is added dropwise at 0°-5° C. a solution of 3-(α,α-dimethylbenzyl)benzenesulphonyl chloride (1.2 g) in dry CH2Cl2 (5 ml) and the reaction mixture is then stirred at 20° C. for 3 hours. The reaction mixture is then diluted by addition of CH2Cl2 (50 ml), washed with brine (3×150 ml) and the organic layer is dried (MgSO4) and concentrated by evaporation to give a solid residue which is purified by chromatography on silica gel using ethylacetate/methanol (9:1) as eluant. Thus is obtained 1-(Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-Nω -nitroarginyl)-4-(ethoxycarbonylmethyl)piperidine as a pale yellow oil, Rf (EtOH)=0.21.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18]Cl.O1CCCC1.[H-].[Na+]>O>[CH2:1]([C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:16][O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(I)cc1Cc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(I)cc1Cc1ccccc1

Procedure:
10.1 g of 2-benzyl-1-hydroxy-4-iodobenzene and 3 ml of chloromethyl methyl ether were added to 100 ml of tetrahydrofuran and while stirring on an ice bath, 1.45 g of 60% (oily) sodium hydride was added dropwise to the mixture. After stirring for 2 hours, water was added to the reaction mixture, which then was extracted with ethyl acetate, washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography with 10% ethyl acetate/hexane, to give 8.7 g of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]3)[C:7]=2[C:6]=1[CH3:33])=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:33])=[C:5]([C:3]([OH:4])=[O:2])[S:32][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:21][C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]2)[CH:16]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Reaction time: 4 h

Procedure:
4-[4-Fluoro-2-((S)-1-methanesulfonyl-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (130 mg) was dissolved in THF (3 ml) and a solution of lithium hydroxide* H2O (60 mg) in water (3 ml) was added. The mixture was stirred for 4 h. HCl (2M) was added to adjusted to pH 5 and the volatile solvent partially removed until crystallization occurred. The solid was collected by filtration. The filter cake was washed with water and was dried to give the desired product.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7](=[O:13])[C:6]=2[CH:14]=1.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC(C)C.[Cu]>[CH3:11][C:9]1([CH3:12])[NH:8][C:7](=[O:13])[C:6]2[CH:14]=[C:2]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: CC1(C)NC(=O)c2cc(I)ccc2O1
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: O
Product: CC1(C)NC(=O)c2cc(Sc3ccccc3)ccc2O1
Yield: 28.4 %

Procedure:
6-Iodo-2,2-dimethyl-3,4-dihydro-2H-1,3-benzoxazin-4-one (compound A-11, 10.0 g), thiophenol (17.2 g), potassium carbonate (10.0 g) and copper powder (1.0 g) were suspended in isoamyl alcohol (100 ml) and the suspension was heated to reflux for 3 hours under Ar. After air cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with an aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane (2:1) to obtain 2,2- dimethyl-6-phenylthio-3,4-dihydro-2H-1,3-benzoxazin-4-one (2.67 g) (Compound A-12). The physical properties are shown in Table 1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: OCCCCCCCCBr
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCCCCCCN1CCOCC1
Yield: 102 %

Procedure:
A solution of 10.0 g (47.8 mmol) of 8-bromo-1-octanol, 10.41 g (120 mmol) of morpholine and tetrahydrofuran was heated to reflux for 3 hr. The cooled reaction mixture was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated to give 10.50 g of 4-(8-hydroxyoctyl)morpholine.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[C:23]#[C:24][C:25](O)(C)C)[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:2].[N:32]1[CH:37]=CC=C[CH:33]=1>>[CH3:33][N:32]([CH3:37])[C:25]#[C:24][CH2:23][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C@@H:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:30][CH3:31])[CH2:8][N:9]1[CH3:29]
Reactant: c1ccncc1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#CC(C)(C)O)c(c34)C[C@H]2N(C)C1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(CC#CN(C)C)c(c34)C[C@H]2N(C)C1

Procedure:
1,1-diethyl-3-[2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]urea, mp starting with 132°-140° C., [α]D =+67.8° (c=0.2% in pyridine);
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])([CH3:4])([CH3:3])[CH3:2].CC(=O)OCC.CC([O-])(C)C.[K+]>[Pd].O=[Pt]=O.C1COCC1>[O:20]=[C:19]1[CH:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[N:8]2[C:16]3[C:11]([CH:10]=[C:9]2[CH2:17][CH2:18]1)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Agent: O=[Pt]=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21

Procedure:
Hydrogenation of the obtained (E)-ethyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-2-yl)acrylate derivatives (4) over a catalyst such as Pd—C 10% or PtO2 in an aprotic solvent such as EA followed by reaction with KOtBu in an aprotic solvent such as THF gives the corresponding tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene and subsequent reductive aminations with, first, benzylamine in the presence of a reducing agent such NaBH(OAc)3 in an aprotic solvent such as DCM, and with, second, an appropriate aldehyde (as precursor of R3) in the presence of a reducing agent such NaBH4 in a protic solvent such as MeOH gives the corresponding N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-amine derivatives (6). Friedel-Craft acylation with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-(benzylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (7). Debenzylation by hydrogenation over a catalyst such as Pd—C 10% in a protic solvent such as EtOH or by reaction with 1-chloroethyl chloroformate and MeOH in an aprotic solvent such as DCM gives the respective N-substituted methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (8). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I) (Method A).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.[OH-].[Na+].Cl.CO.[CH3:21][NH2:22]>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:22][CH3:21])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1cc(OC)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 1.00 g portion of 4-chloro-2-methoxy-5-nitrobenzoic acid and 0.52 g of sodium hydroxide were dissolved in 20 ml of 40% methylamine methanol solution, followed by stirring at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured on crushed ice and adjusted to pH 4 with 6N hydrochloric acid aqueous solution. The thus precipitated product of interest was collected by filtration, washed with water and dried under a reduced pressure and then the resulting crude product was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 0.30 g of 2-methoxy-4-methylamino-5-nitrobenzoic acid.