Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O[Si](C)(C)C)([C:12]#[N:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[I-].[Na+]>O>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:12]#[N:13])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)OCCC2(C#N)O[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)OCCC2C#N

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 2, by 1) the reaction of 1.0 gram (0.006 mole) of 7-methylchroman-4-one (ii) with 1.8 gram (0.018 mole) of trimethylsilyl cyanide, in the presence of 0.2 gram (catalyst) of aluminum chloride in 30 mL of toluene, affording an intermediate product, namely: 7-methyl-4-(1,1-dimethyl-1-silaethoxy)chromane-4-carbonitrile (cyano-silyl intermediate), then 2) the reaction of the 1-silaethoxy intermediate with 3 mL (0.024 mole) of trimethylsilyl chloride, 3.6 grams (0.024 mole) of sodium iodide, and 0.2 mL of water in 30 mL of acetonitirile, yielding 0.8 gram of subject compound. Contrary to Step E of Example 2, the hydrogenation step was not necessary to obtain the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [S:1]1[CH:5]=[C:4](B(O)O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22](Br)=[N:23][CH:24]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[S:1]1[CH:5]=[C:4]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)=[CH:24][N:23]=2)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)csc2c1

Procedure:
Synthesized using benzo[b]thiophen-3-ylboronic acid (224 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 100 mg, 0.34 mmol, 54%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.27 (s, 2H), 6.99 (t, J=1.3 Hz, 1H), 7.18 (brs, 1H), 7.39-7.42 (m, 1H), 7.43-7.47 (m, 1H), 7.59 (dd, J=8.2, 2.5 Hz, 1H), 7.70 (dd, J=8.2, 0.9 Hz, 1H), 7.82 (s, 1H), 7.90-7.92 (m, 1H), 8.01 (s, 1H), 8.46-8.48 (m, 1H), 8.66-8.67 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=45.5, 119.3, 122.6, 122.8, 124.1, 124.7, 124.8, 127.1, 128.7, 129.4, 135.7, 135.9, 137.0, 137.1, 140.9, 148.6, 155.0; MS (ESI): m/z=292.05 [M+H]+.
Reaction SMILES: C[Se:2][CH2:3][C@H:4]([NH2:8])[C:5]([OH:7])=[O:6].Cl.[CH3:10]OC(=O)[C@H](C)N[Cl:15].Cl.ClN[C@H](C(O)=O)C.ClN[C@H](C(O)=O)C.C[Se]>CO>[ClH:15].[CH3:10][NH:8][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][SeH:2]
Reactant: C[Se]C[C@H](N)C(=O)O
Reactant: COC(=O)[C@H](C)NCl
Agent: C[C@H](NCl)C(=O)O
Agent: C[Se]
Agent: Cl
Solvent: CO
Product: CN[C@@H](C[SeH])C(=O)O

Procedure:
A process for manufacturing L-Se-methylselenocysteine by reaction of chloroalanine methyl ester hydrochloride or chloroalanine hydrochloride or chloroalanine with methylselenol or its salts in a solvent, acidifying the reaction mixture after completion of reaction, isolating methyselenocysteine hydrochloride as a methanol solution, neutralizing the methanol solution with triethyl amine to precipitate L-Se-methylselenocysteine.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][CH:21]=[N:22]4)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](C1C(N[C@@H](C2C=CC=CC=2)C)=NC(C2C=CC=C3C=2C=CC=N3)=CC=1)([O-])=O.[CH2:55]([OH:57])C>[Pd]>[C:1]1([C@H:7]([N:9]2[C:10]3=[N:11][C:12]([C:17]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:18]=4[CH:19]=[CH:20][CH:21]=[N:22]5)=[CH:13][CH:14]=[C:15]3[NH:16][C:55]2=[O:57])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](Nc1nc(-c2cccc3ncccc23)ccc1N)c1ccccc1
Reactant: CCO
Agent: [Pd]
Agent: C[C@@H](Nc1nc(-c2cccc3ncccc23)ccc1[N+](=O)[O-])c1ccccc1
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(-c3cccc4ncccc34)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
(R)—N2-(1-Phenylethyl)-6-(quinolin-5-yl)pyridine-2,3-diamine. A solution of (R)-3-nitro-N-(1-phenylethyl)-6-(quinolin-5-yl)pyridin-2-amine (1.10 g, 2.97 mmol) in ethanol (95 mL) was purged with nitrogen for several minutes. Following addition of palladium on carbon (0.125 g, 1.18 mmol), the flask was evacuated and a hydrogen filled balloon was placed on the reaction. After stirring at room temperature for 18 h, the reaction was filtered and the solvent removed under reduced pressure to afford the title compound (0.77 g, 76% yield). MS (ESI) m/z 341.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CCC2(C)c3ccc(S)cc3CCC12
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][C:9]([O:11]C)=O)[CH2:2]1.[NH3:13]>CO>[NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][CH2:8][C:9]([NH2:13])=[O:11])[CH2:2]1
Reactant: N
Reactant: COC(=O)CCC1CNCCO1
Solvent: CO
Product: NC(=O)CCC1CNCCO1
Yield: 78 %

Procedure:
Methyl 3-(morpholin-2-yl)propanoate (0.58 g, 3.35 mmol) was reacted with a solution of NH3 in methanol (7 mol/L, 10 mL) according to the procedure as described in Example 25, Step A to give the title compound as brownish oil (0.41 g, 78%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH2:10]([N:12]1[C:18]2[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:17]=2[CH2:16][N:15]([CH2:24][CH3:25])[CH2:14][CH2:13]1)[CH3:11].C(O)C>>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[CH:21]=[CH:22][C:17]3[CH2:16][N:15]([CH2:24][CH3:25])[CH2:14][CH2:13][N:12]([CH2:10][CH3:11])[C:18]=3[CH:19]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Solvent: CCO
Product: CCN1CCN(CC)c2cc(Nc3nc(Cl)ncc3Cl)ccc2C1
Temperature: 80 °C
Yield: 65.2 %

Procedure:
Into a Round bottom flask was added 2,4,5-Trichloro-pyrimidine (0.34 g, 0.0018 mol), 1,4-Diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-ylamine (0.40 g, 0.0018 mol) and Ethanol (25 mL, 0.43 mol) and was heated at 80° C. for 3 hour. The reaction was evaporated and the residue treated with a sodium carbonate solution, extracted with EtOAc, washed with water, dried and evaporated to give a solid. This was chromatographed on a SiO2 prep plate with DCM/10% ammonia/methanol (10-1) giving (2,5-Dichloro-pyrimidin-4-yl)-(1,4-diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-8-yl)-amine as a tan solid (0.43 g, 63%). Mp 69-73° C.; LCMS (m/e) 366 (M); 1H-NMR (DMSO, 400 MHz) δ 9.39 (s, 1H), 8.36 (s, 1H), 7.19 (s, 1H), 7.13-7.11 (d, 1H, J=8.08 Hz), 7.05-7.03 (D, 1H, J=7.83 Hz), 3.62 (s, 2H), 3.20-3.15 (q, 3H, J=7.08 Hz), 3.02-2.95 (br, 2H), 2.84-2.76 (br (s, 2H), 2.49-2.40 (br, 2H), 1.20-1.16 (t, 3H, J=7.07 Hz), 1.06-1.02 (t, 3H, J=7.08 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:11])=[O:10].[N:17]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][N:17]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: COC(=O)CS(=O)(=O)c1cc(C)ccc1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C1=NNc2ccc(C)cc2S1(=O)=O
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of methyl ((2-amino-5-methylphenyl)sulfonyl)acetate (Preparation 38, 1.5 g) in glacial acetic acid (20 mL) is added dropwise with vigorous stirring to a mixture of sodium nitrite (0.47 g) in water (6 mL) at room temperature. The mixture is stirred for 1 h. The resulting precipitate is filtered and washed with excess water. The solid is collected and placed under high vacuum overnight to obtain 1.05 g (67%) of the title compound as a green powder. Physical characteristics: MS (ESI−) m/z 253 (M−H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([O:22][CH2:23][CH2:24][O:25][C:26]4[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)=[N:17][N:18]([CH3:21])[C:19]=3[NH2:20])=[CH:14][C:9]=2[O:8][CH2:7]1.CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]([O:22][CH2:23][CH2:24][O:25][C:26]4[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=4)=[N:17][N:18]([CH3:21])[C:19]=3[N:20]([S:2]([CH3:1])(=[O:4])=[O:3])[S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cn1nc(OCCOc2ncc(Cl)cn2)c(-c2ccc3c(c2)OCO3)c1N(S(C)(=O)=O)S(C)(=O)=O
Reaction time: 24 h

Procedure:
Methanesulfonyl chloride (20 ul) was added at room temperature under an atmosphere of nitrogen to a mixture of 4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-ylamine (50 mg) (Preparation 48), dimethylaminopyridine (16 mg) in anhydrous pyridine (2.4 ml) and the reaction was stirred for 24 h. The mixture was concentrated under reduced pressure, then a saturated solution of ammonium chloride (6 ml), ethyl acetate (6 ml), and brine (6 ml) were sequentially added to the residue. The aqueous phase was extracted with ethyl acetate (2×8 ml) and the combined organic fractions were washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The oil was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) to yield the title compound as a pale yellow oil (71 mg).
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][NH2:43])[CH:39]=[CH:40][CH:41]=1)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[NH2:31][C:32]([NH:34][CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][NH:43][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:27][N+:28]([O-:30])=[O:29])[NH:8][C:9](=[O:23])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:39]=[CH:40][CH:41]=1)=[O:33]
Reactant: NCc1cccc(CNC(N)=O)c1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: NC(=O)NCc1cccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)c1
Yield: 50 %

Procedure:
Prepared analogously to Example 4b) from (R)-N5 -[amino(nitroimino]methyl]-N2 -(diphenylacetyl)-ornithine, 3-(amino-carbonylaminomethyl)benzenemethanamine and TBTU in a yield of 50% of theory. Colourless amorphous substance.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:12]([O-])=O)[CH:5]=[N:4]1)[CH3:2]>CO.[Pd]>[NH2:12][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCn1ncc([N+](=O)[O-])c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCn1ncc(N)c1C(=O)OC
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A mixture of methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylate (2.2 g) and 10% Pd—C (0.60 g) in MeOH (30 mL) was hydrogenated under balloon pressure at room temperature overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(F)c(-c2ccccc2)c1
Temperature: 60 °C
Yield: 68.4 %

Procedure:
A mixture of 18.5 g of 4-fluoro-3-phenylnitrobenzene, 76.7 g of stannous chloride dihydrate and 150 ml concentrated hydrochloric acid was heated at 60° C. for 2 hours with stirring. After cooling, the resulting precipitate was dissolved in water and the mixture was basified with sodium carbonate. The mixture was extracted five times with chloroform and the combined organic extracts were dried and evaporated to yield the product as a pale brown oil (10.9 g, yield 68%) which was used without further purification. NMR (CDCl3, 60 MHz): 7.15 (m, 5H), 7.1-6.1 (m, 3H), 3.3 (br,s, 2H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]3)[N:12]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: Nc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
A suspension of tert-butyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.4 mmol), 4-aminophenylboronic acid, pinacol ester (0.69 g, 3.2 mmol), and tetrakis(triphenylphosphine) palladium (0.28 g, 0.24 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound.
Reaction SMILES: [NH:1]([C:5]1[C:18]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[O-:20][Si]([O-])=O.[Na+].[Na+].OO>O>[NH:1]([C:5]1[C:18]2[C:17](=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1cccc2c1Cc1ccccc1C2=O
Reactant: O=[Si]([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 94.3 %

Procedure:
125.5 g (0.5 mole) of 4-acetamino-anthrone in 1.5 liters of water are warmed to 70°. 50 ml of sodium water glass are added (d = 1.35) and 400 ml of a hydrogen peroxide solution which contains 80 g of H2O2 per liter are then allowed to run in dropwise in the course of 1 hour. Appropriately, a slight stream of nitrogen is passed over the surface during the reaction. The mixture is then stirred at between 70° and 90° C until no further starting material is found in a sample which is withdrawn and examined by thin layer chromatography. In the course of the oxidation, the suspension has developed an intense yellow color. The suspension is filtered and the product washed until neutral. After drying, 125 g of 1-acetamino-anthraquinone with a melting point of 221° C are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=[O:9])=[O:4]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
Methylchloroformate (14.5 mL, 0.188 mol) was added over 15 min to a cooled (0-6° C.) mixture of (S)-2-amino-3-methyl-butyric acid (20.0 g, 0.171 mol), NaOH (6.80 g, 0.171 mol) and sodium carbonate (18.1 g, 0.171 mol) in water (200 mL). The cooling bath was removed and the mixture was stirred at ambient temperature overnight. Conc. aqueous HCl (30 mL) was added to the reaction mixture to adjust pH to ˜1. A solid formed and the mixture was stirred for 90 min. The mixture was filtered and the solid was dried overnight under reduced pressure at 40° C. t to provide the title intermediate (27.8 g, 93% yield). 1H NMR (CD3OD, 400 MHz) δ (ppm) 4.87 (br. s, 2H), 4.05 (d, J=5.49, 1 H), 3.65 (s, 3 H), 2.25-2.05 (m, 1 H), 0.98 (d, J=6.87, 3 H), 0.94 (d, J=6.87, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:27](Cl)(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:27]([NH:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)(=[O:29])=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1
Reactant: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Cl)cc1F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: Cn1nccc1-c1cc(-c2ccccc2)ccc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F

Procedure:
A solution of 3-fluoro-4-{[3-(1-methyl-1H-pyrazol-5-yl)biphenyl-4-yl]oxy}benzenesulfonyl chloride (Preparation 31, 350 mg, 0.79 mmol) and 2-amino thiazole (158 mg, 1.58 mmol) in pyridine (2 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue acidified to pH 4-5 with a 1M aqueous solution of hydrogen chloride. The mixture was extraction with ethyl acetate (3×10 mL). The organic layer was separated and washed sequentially with water (3×5 mL) and brine (1×5 mL), then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 35% ethyl acetate in hexane) followed by trituration with pentane to afford the title compound as an off white solid (75 mg, 19%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.NC(N)=[S:22]>COCCO.O>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2](=[S:22])[NH:3][N:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH3:17]
Reactant: NC(N)=S
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Solvent: COCCO
Solvent: O
Product: CCCOc1ccc(-c2ccc(=S)[nH]n2)cc1OC

Procedure:
T13.9 g of 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine are boiled under reflux with 5.5 g of thiourea in 50 ml of ethylene glycol monomethyl ether for 8 hours. After cooling, the mixture is diluted with 250 ml of water and extracted three times with chloroform. The chloroform extracts are dried over sodium sulfate and evaporated. The residue is crystallized from ethanol/ethyl acetate. 4.8 g (34.6% of theory) of the title compound of m.p. 174°-17620 are obtained.
Reaction SMILES: N#N.C([NH:6][C:7]1[NH:8][C:9](=[O:23])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])[C:14]=2[N:15]=1)(=O)C>N>[OH:20][CH2:19][CH:18]([O:17][CH2:16][N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:23])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2)[CH2:21][OH:22]
Reactant: CC(=O)Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Agent: N
Agent: N#N
Product: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Yield: 95.1 %

Procedure:
N2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4 mmol) was stirred with 50 ml of methanolic ammonia solution (methanol saturated with ammonia at 0° C.) for 17 hours at 21° C. The solution was concentrated to a white solid and the residue recrystallized from water or methanol to give 582.3 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250° C. d.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:13])[CH2:12][Br:14])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(C)=O)s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(=O)CBr)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 40.3 g of 2-acetylaminomethyl-5-acetylthiophene in 500 ml of chloroform is added dropwise bromine under cooling with ice at 5°-10° C., and the mixture is stirred at room temperature for 30 minutes. After the resulting mixture is washed with water, dried over anhydrous magnesium sulfate and concentrated, the residue is recrystallized from ethanol to give 2-acetylaminomethyl-5-bromoacetylthiophene, melting at 129°-131° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][CH2:28][CH2:29][N:30]([CH2:34][CH2:35][Cl:36])[C:31](Cl)=[O:32]>N1C=CC=CC=1>[Cl:27][CH2:28][CH2:29][N:30]([CH2:34][CH2:35][Cl:36])[C:31]([O:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:24]=1)=[O:32]
Reactant: O=C(Cl)N(CCCl)CCCl
Reactant: Cc1ccc(O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)N(CCCl)CCCl)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (U.S. Pat. No. 3,299,104), tert-butyl 3-[5-[bis(2-chloroethyl)carbamoyloxy]-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)butanoate (23e) is prepared through carbamoylation of tert-butyl 4-(tert-butoxycarbonylamino)-3-(5-hydroxy-2-methyl-phenyl)butanoate (23d) (731 mg, 2.0 mmol) with commercial N,N-bis(2-chloroethyl)carbamoyl chloride (439 μL, 614 mg, 3.0 mmol) in anhydrous pyridine (15 mL) at about 0° C. The reaction mixture is stirred with gradual warming to room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Excess of the carbamoyl chloride is destroyed with crushed ice. Aqueous work-up followed by purification through silica gel column chromatography afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(F)cc1C
Yield: 99.7 %

Procedure:
1-Fluoro-4-methoxy-5-methyl-2-nitro-benzene (1.18 g, 6.4 mmol) was dissolved in 40 ml of methanol at room temperature. 10% Palladium on Carbon (200 mg) was added and the mixture was stirred under a balloon of hydrogen overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo to give 2-fluoro-5-methoxy-4-methyl-phenylamine (990 mg, quantitative) as a solid.