Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[S:30][CH3:31])=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2].C1(C2[O:46]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl>[C:1]([C:3]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[C:12]([C:21]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[S@:30]([CH3:31])=[O:46])=[O:22])[C:13](=[O:20])[N:14]3[C:19]=2[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH2:5][CH2:4]1)#[N:2]
Reactant: CS[C@@H]1CCCC[C@H]1NC(=O)c1cc(CN2CCC(C#N)(c3ccccn3)CC2)c2ccccn2c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: C[S@](=O)[C@@H]1CCCC[C@H]1NC(=O)c1cc(CN2CCC(C#N)(c3ccccn3)CC2)c2ccccn2c1=O
Reaction time: 0.75 h

Procedure:
To a solution of rac-1-[(4-cyano-4-pyridin-2-ylpiperidin-1-yl)methyl]-N-[(1R,2R)-2-(methylthio)cyclohexyl]-4-oxo-4H-quinolizine-3-carboxamide (Example 16, 0.035 g, 0.067 mmol) in 2 mL of dichloromethane at 0° C. was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (Davis reagent, 0.019 g, 0.074 mmol). After 45 min, the mixture was washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave a proton NMR spectra consistent with theory and a high resolution mass spectrum (ES+) m/z of 532.2390 calculated for M+H+ [C29H34N5O3S: 532.2377]: 1H NMR (400 MHz, CDCl3) δ 10.02-9.99 (m, 1H), 9.42-9.40 (m, 1H), 8.66 (s, 1H), 8.60-8.57 (m, 1H), 8.22-8.19 (m, 1H); 7.76-7.67 (m, 2H), 7.62-7.60, 7.32-7.21 (m, 1H), 4.29-4.26 (m, 1H), 4.13-4.03 (m, 1H), 3.81 (s, 2H), 3.01-2.83 (m, 2H), 2.82-2.78 (m, 1H), 2.61 (s, 3H), 2.47-2.43 (m, 1H), 2.32-2.26 (m, 2H), 2.14-2.06 (m, 4H), 2.05-1.84 (m, 2H), 1.83-1.36 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:20]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]([O:12][CH3:20])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN(C)CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCCN(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
To (S)-2-(tert-butoxycarbonylamino)-5-(dimethylamino)pentanoic acid (129 mmol, 1.0 eq) in MeOH (130 mL) under N2 (g) at 0° C. was added TMSCHN2 (84 mL, 168 mmol, 1.3 eq, 2.0 M in diethyl ether) slowly via addition funnel over 40 minutes. The ice-water bath was removed and the reaction mixture was warmed to room temperature and stirred 16 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (250 mL) and satd NaHCO3 (200 mL). Additional H2O was added to form a clear aqueous layer, which was extracted with EtOAc (2×175 mL). The combined extracts were then washed with additional satd NaHCO3 (100 mL) and brine, dried over MgSO4, filtered and concentrated to afford (S)-methyl 2-(tert-butoxycarbonylamino)-5-(dimethylamino)pentanoate (16.8 g, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.85 (d, J=6.8 Hz, 1H), 4.15-4.04 (m, 1H), 3.58 (s, 3H), 2.12 (t, J=6.9 Hz, 2H), 2.06 (s, 6H), 1.73-1.51 (m, 4H), 1.29 (s, 9H); MS (EI) m/z 275 (MH+).
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[S:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[S:28]>C(O)(=O)C>[C:1]1([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[C:32]3[S:26][C:27](=[S:28])[NH:29][C:30]3=[O:31])=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(OCc2cccc3ccccc23)cc1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc(OCc2cccc3ccccc23)cc1

Procedure:
Under a nitrogen atmosphere in a round bottom flask 4-[(naphth-1-yl)methoxy]benzaldehyde (5.25 g, 20 mmol) was dissolved in 100 ml of acetic acid. To this solution was added sodium acetate (5.74 g, 70 mmol) and rhodanine (2.66 g, 20 mmol). The reaction mixture was raised to the reflux temperature and maintained at this temperature. The progress of the reaction was monitored by thin layer chomratography.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14][C:15]3[S:16][C:17]([C:23]4[N:27]=[CH:26][N:25](COCC[Si](C)(C)C)[N:24]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>CCO>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14][C:15]3[S:16][C:17]([C:23]4[N:27]=[CH:26][NH:25][N:24]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:11]=[CH:10][N:9]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOCC4)n3)s2)n1
Agent: Cl
Solvent: CCO
Product: NC(=O)c1cc(-c2nc[nH]n2)sc1Nc1ccnc(CN2CCOCC2)n1
Temperature: 60 °C

Procedure:
2-{[2-(Morpholin-4-ylmethyl)pyrimidin-4-yl]amino}-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)thiophene-3-carboxamide (100 mg, 0.19 mmol) was taken up in a mixture of EtOH (3.0 mL) and HCl (2.0 M, 3.00 mL, 6.00 mmol) and heated to 60° C. overnight. The reaction was not complete, so the temperature was raised to 75° C. for 6 h. The resulting suspension was filtered to isolate the title compound as a pale yellow solid (HCl salt).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccccc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (68 mg, 88%), MS (ISP) m/z=311.5 [(M+H)+], mp 230.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: S.C([C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(C)(C)C>>[CH:13]1[C:12]2[C:11](=[O:21])[C:10]3[C:19](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:18](=[O:20])[C:17]=2[CH:16]=[CH:15][CH:14]=1.[CH:15]1[CH:16]=[C:17]2[C:18]([OH:20])=[C:19]3[C:10](=[C:11]([OH:21])[C:12]2=[CH:13][CH:14]=1)[CH:9]=[CH:8][CH:7]=[CH:6]3
Reactant: CC(C)(C)c1cccc2c1C(=O)c1ccccc1C2=O
Agent: S
Product: O=C1c2ccccc2C(=O)c2ccccc21
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
H2S and t-butyl anthraquinone are dissolved in several solvents. They are then reacted in the H2S reactor at optimum conditions to determine which combination of reactants and solvents yields the greatest conversion of anthraquinone to anthrahydroquinone. The results are set forth in Table 1 below.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:29]3[C:30]4[C:26](=[CH:25][C:24]([O:23][CH3:22])=[CH:32][CH:31]=4)[CH:27]=[CH:28]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: COc1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 5-methoxy-1H-indole (0.085 g, 20%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:32])[CH2:6][CH2:7][C:8]([C:30]#[N:31])([C:15]1[C:23]2[C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][C:19]=2[C:18]([O:28][CH3:29])=[CH:17][CH:16]=1)[CH2:9][CH2:10][C:11](OC)=[O:12]>COCOC>[CH3:3][O:4][C:5]([CH:6]1[CH2:7][C:8]([C:30]#[N:31])([C:15]2[C:23]3[C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[O:20][C:19]=3[C:18]([O:28][CH3:29])=[CH:17][CH:16]=2)[CH2:9][CH2:10][C:11]1=[O:12])=[O:32]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC)c2oc3ccccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: COCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c3oc4ccccc4c23)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 50% NaH (4.6 g, 0.097 mol) in dimethoxymethane (20 ml) at room temperature under nitrogen was added drop wise at room temperature and under nitrogen a solution of 4-cyano-4-(4-methoxy-dibenzofuran-1-yl)-heptane dioic acid dimethyl ester (13.3 g, 0.032 mol) in dimethoxymethane (130 ml). The reaction mass was allowed to stir for 3 hrs at room temperature. Once product is formed, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated under vacuum. 5-cyano-5-(4-methoxy-dibenzofuran-1-yl)-2-oxo-cyclohexane carboxylic acid methyl ester was isolated by column chromatography. Yield 9.8 g (80%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(Cl)(=O)[C:16](Cl)=[O:17]>C(Cl)CCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:16]=[O:17])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-fluoro-3-(trifluoromethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.Cl.[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])[CH3:14]>CN(C=O)C.O>[CH2:13]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH:19][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:14]
Reactant: CCOC(=O)CCN
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1c(C)cccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 76.6 %

Procedure:
1-Methyl-2-fluoro-3-nitro-benzene (465 mg, 3 mmol) was dissolved in DMF (6 mL) and 3-aminopropionic acid ethyl ester hydrochloride salt (735 mg, 4.6 mmol) was added followed by TEA (1.5 mL, 10.7 mmol). The reaction mixture was heated in the microwave at 130° C. for 1 h, cooled, diluted with water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with 1 N HCl (30 mL), water (30 mL) and brine (30 mL), dried and evaporated to provide 3-(2-methyl-6-nitrophenylamino)-propionic acid ethyl ester (580 mg, 77% yield) which was used directly. This intermediate (101 mg, 0.4 mmol), ammonium formate (252 mg, 4 mmol) and Pd/C (5%, 5 mg) were combined in a reaction vial and methanol (1 mL) was added. The mixture was agitated at room temperature for 4 h, diluted with dichloromethane (5 mL) and filtered, and the mother liquors were concentrated to provide the crude product 3-(2-amino-6-methylphenylamino)-propionic acid ethyl ester which was used directly. This intermediate (37 mg, 0.17 mmol) was dissolved in dichoromethane (1 mL) and carbonyldiimidazole (34 mg, 0.21 mmol) was added. The resulting mixture was agitated at room temperature overnight then purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the intermediate 3-(7-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propionic acid ethyl ester (21 mg, 51% yield) which was used directly. This intermediate was dissolved in DMF (1 mL), and K2CO3 (69 mg, 0.5 mmol) was added followed by (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (137.7 mg, 0.4 mmol), prepared as described previously. The resulting mixture was heated at 65° C. overnight, cooled, filtered and the solution was treated directly with Amberlyst® A26 (OH—) (650 mg, 0.87 mmol). This reaction mixture was agitated overnight and the resin was filtered and washed with several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×2 mL) and washing with methanol (2 mL). The combined eluant and final wash was evaporated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (9 mg, 15% yield). LCMS (ESMS): m/z 378 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 76 %

Procedure:
The II-B isomer (2.9 g, 0.01 mole; m.p. 78°-79° C.) of 1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-one (Compound No. 1') was dissolved in methanol (50 ml). The isomer was allowed to react with sodium borohydride and then treated in the same manner as in Example 1. The residue obtained was recrystallized from a 1:10 mixture of carbon tetrachloride and n-hexane to obtain 2.2 g (yield 76%) of the I'-B isomer (m.p. 116°-117° C.) of Compound No. 1. The elementary analysis and NMR spectrum of the compound are shown below.
Reaction SMILES: COC1C=C(C(Cl)=O)C=CC=1OC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:42]=[CH:43][C:44]=1[O:45][CH3:46].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[C:30]([F:36])[CH:31]=1)=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: COc1ccc(C(=O)N=C=S)cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 63%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([S:13]([N:16]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=[O:24])=[CH:17]2)(=[O:15])=[O:14])=[CH:10][CH:9]=1.[NH2:26][OH:27]>O>[OH:27][NH:26][C:23](=[O:24])/[CH:22]=[CH:21]/[C:18]1[CH:19]=[CH:20][N:16]([S:13]([C:11]2[S:12][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:9][CH:10]=2)(=[O:15])=[O:14])[CH:17]=1
Reactant: O=C(Cl)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1
Reactant: NO
Agent: Cl
Solvent: O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1)NO
Temperature: 0 °C
Reaction time: 1.08 h

Procedure:
The above prepared solution of (E)-3-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acryloyl chloride hydrochloride was added to an aqueous hydroxylamine solution (50%, 150 g, 2.27 mop at 20-25° C. over a period of 45 min. After stirring for 65 min, water (300 mL) was added and cooled to 0° C. The suspension was filtered and the filter cake was washed with water (150 mL). The title compound was obtained as beige solid (17.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:32]([BH3-])#N.[Na+]>CO.CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:12]([C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH3:27])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:29])[C:18](=[O:28])[NH:19][N:20]=2)[CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2c(cc1NC1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2c(cc1N(C)C1CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.40 mmol) and paraformaldehyde (neat, 0.024 g, 0.80 mmol) in MeOH (10 mL) and HOAc (1 mL) was heated at 70° C. for 14 h. The mixture was cooled to ambient temperature and sodium cyanoborohydride (0.050 g, 0.80 mmol) was added. The resulting dark solution was stirred at 70° C. for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 33-60% EtOAc in petroleum ether) to give 3-[(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-methyl-amino]-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.081 g, 49%). LC/MS (Table 1, Method 2) Rt=1.168 min.; MS m/z: 416 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:6]([CH2:12]Cl)=[N:7]2.[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2[NH2:33])[NH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:33][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:26]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:25]=[C:24]([I:23])[C:32]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred mixture of 5-bromo-3-(2-chlorobenzyl)-2-(chloromethyl)quinazolin-4(3H)-one, (2), (13.6 g, 30.7 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3) (8.09 g, 30.7 mmol) in DMF (300 mL was added potassium carbonate (6.36 g, 46.0 mmol) and the reaction maintained at RT in the dark for 24 hr. The mixture was poured onto water (4.0 L) and the resulting suspension was stirred at RT for 1 hr. The precipitate was isolated by filtration and dried in vacuo to afford the title compound, (4), as a colourless solid (18.0 g, 94%); Rt 2.17 min; m/z 622/624 [M+H]+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8]COC)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:19](I)[CH3:20].C(=O)([O-])[O-].[K+].[K+].S(=O)(=O)(O)O>C(O)C.O.CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCI
Reactant: CCOC(=O)CCc1ccc(OCOC)cc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)cc1OCC
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.7 %

Procedure:
A mixture of ethyl 3-(2-hydroxy-4-methoxymethoxyphenyl)propionate (6.00 g), ethyl iodide (5.52 g), anhydrous potassium carbonate (3.26 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 13 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil. A mixture of the obtained oil, 10% aqueous sulfuric acid solution (10 mL) and ethanol (300 mL) was stirred with heating under reflux for 6 hrs. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water, and then basified with a saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-(2-ethoxy-4-hydroxyphenyl)propionate as a colorless oil (3.58 g, 64%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.Cl.[CH2:15](N=C=NCCCN(C)C)[CH3:16].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:15]([O:12][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)=[O:13])[CH3:16]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cn1ccc2ccc(C(=O)O)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ccc2ccn(C)c2c1
Reaction time: 15 h
Yield: 88.6 %

Procedure:
A solution of 1.05 g (6.0 mmol) of 1-methyl-1H-indole-6-carboxylic acid in 15 mL of methylene chloride was added to a stirring solution of 1.905 g (10 mmole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1.20 g (10 mmole) of 4-dimethylaminopyridine in 20 mL of methylene chloride at room temperature. Ethanol was added and the reaction stirred for 15 h. The reaction mixture was extracted with ethyl acetate, the organic phase was washed with brine and dried on anhydrous magnesium sulfate. Chromatographic purification of this material gave 1.08 g (89%) of 1-methyl-1H-indole-6-carboxylic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([O:46][Si](C(C)(C)C)(C)C)([C:42]([F:45])([F:44])[F:43])[C:38]([F:41])([F:40])[F:39].C(OCC)(=O)C>C1COCC1>[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([OH:46])([C:38]([F:39])([F:40])[F:41])[C:42]([F:44])([F:45])[F:43]
Reactant: CSc1ccc(Sc2ccc(NC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(Sc2ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Yield: 89.4 %

Procedure:
Tetra-n-butylammonium fluoride (0.48 ml of a 1M solution in THF) was added to a stirred solution of N-[2-fluoro-4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-(t-butyldimethylsilyloxy)-2-trifluoromethyl-3,3,3-trifluoropropanamide (0.278 g) (Method 55) in anhydrous THF (5 ml) at −78° C. under argon. After 30 minutes ethyl acetate (50 ml) was added and the mixture was washed with aqueous hydrochloric acid (2M, 30 ml) and brine (30 ml) then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluting with 10-30% ethyl acetate/iso-hexane to give the title compound (0.199 g) as a pale yellow solid. NMR (CDCl3): 2.50 (s, 3H), 5.12 (s, 1H), 6.98 (d, 1H), 7.05 (d, 1H), 7.23 (d, 2H), 7.35 (d, 2H), 8.05-8.09 (m, 1H); MS (ESP−): 458.