Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6]([N:9]([CH:28]([CH3:30])[CH3:29])[CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)([CH3:8])[CH3:7].C1C=CC=CC=1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>O>[CH3:37][N:38]([CH3:42])[C:39]([N:12]([CH2:11][CH2:10][N:9]([CH:6]([CH3:7])[CH3:8])[CH:28]([CH3:30])[CH3:29])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:14]=1)=[O:40]
Reactant: Cc1cc(OCc2ccccc2)nc(NCCN(C(C)C)C(C)C)n1
Reactant: CN(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(OCc2ccccc2)nc(N(CCN(C(C)C)C(C)C)C(=O)N(C)C)n1

Procedure:
Under a nitrogen atmosphere, n-butyl lithium solution (22.2 ml, 0.036 mole) is added dropwise with stirring to a solution of 2-(2-diisopropylaminoethylamino)-4-methyl-6-benzyloxypyrimidine (12.4 g, 0.036 mole) in 75 ml. of dry benzene at 25° to 30° C. with occasional cooling over a 20 minute period. After stirring an additional 3/4 hour, dimethylcarbamoyl chloride (4.3 g, 0.04 mole) is added dropwise over 15 minutes. The reaction is stirred at room temperature for 16 hours. After cooling, the reaction mixture is treated with water and the benzene layer is separated. The crude product is extracted into 1 N-hydrochloric acid. This aqueous solution is basified and the product is extracted into ether, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel eluting with 25% methanol, 75% chloroform yields N,N-dimethyl-N'-(2-diisopropylaminoethyl)-N'-(4-methyl-6-benzyloxy-2-pyrimidinyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][CH:16]([N:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:22]=5[NH:21][C:20]4=[O:32])[CH2:15][CH2:14]3)[CH:8]=2)=[CH:4][C:3]=1[CH3:35].[CH3:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:22]2[NH:21][C:20](=[O:32])[N:19]([CH:16]3[CH2:15][CH2:14][N:13]([C:9]4[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]5[CH:33]=[CH:34][C:2]([NH:1][C:37](=[O:38])[CH3:36])=[C:3]([CH3:35])[CH:4]=5)[CH:8]=4)[CH2:18][CH2:17]3)[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(N)c(C)c4)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(NC(C)=O)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
80 mg (0.17 mmol) 3-(1-(6-(4-amino-3-methylphenoxy)pyrimidin-4-yl)piperidin-4-yl)-7-methoxy-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one, 0.02 mL (0.35 mmol) AcOH, 120 mg (0.37 mmol) TBTU and 0.06 mL (0.43 mmol) TEA in 2.0 mL DMF were stirred for 2 h at RT. Water was added to the reaction mixture. The precipitate was suction filtered and purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][OH:7].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH2:6][O:7][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCOc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a stirred solution of (S)-(tert-butoxycarbonylamino)-4-hydroxybutyric acid methyl ester (1.43 g; CAS 120042-11-7) in THF (4 ml) were added phenol (692 mg), triphenylphosphine (1.77 g) and diisopropyl azodicarboxylate (1.36 g). The resulting yellow solution was stirred at room temperature overnight. The reaction mixture was evaporated and purified by column chromatography (SiO2; gradient: heptane/EtOAc 100:0->90:10) to give (S)-2-tert-butoxycarbonylamino-4-phenoxy-butyric acid methyl ester (1.16 g, 61%) as a light yellow oil. MS (ISP): 210.1 ([M+H-BOC]+)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:11][CH2:12]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1CSCCN1
Product: N#Cc1ccc(N2CCSCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and thiomorpholine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].Cl[C:13]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.S(Cl)(Cl)=O>CS(C)=O.CO>[CH3:9][O:8][C:6]([C:2]1[N:1]([C:13]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(-n2cccc2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
Methyl 1H-pyrrole-2-carboxylate (5.78 g, 46.2 mmol) was dissolved in DMSO and cooled to 10° C. NaH was added in two portions over 5 min. The reaction mixture was stirred at 10° C. for 10 min and methyl 6-chloro-5-nitronicotinate (5 g, 23.09 mmol) in DMSO (10 mL) was added slowly over 3 min. The red reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C. and quenched with water (12 mL) and diluted with brine (50 mL). The mixture was washed with EtOAc (2×25 mL) and the aqueous layer was acidified to pH=2 with 4.5 N HCl. It was extracted with EtOAc (1×100 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow solid, which was dissolved in MeOH (100 mL) and cooled to 0° C. Thionyl chloride (45 mL, 617 mmol) was added slowly over 5 min. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. It was concentrated in vacuo and the resulting solid was triturated with ethyl acetate (300 mL). The solid was filtered off and the filtrate was concentrated in vacuo. then washed with ethyl ether to afford methyl 6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.04 g, 16.51 mmol, 92% yield) as a yellow solid, [M+H] calc'd for C13H11N3O6, 306; found, 306.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2cc(O)ccc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(O)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 6-methoxynaphthalen-2-ol (2.00 g, 11.5 mmol) in DMF (20 mL) was added NBS (2.15 g, 12.1 mmol) and the reaction mixture was stirred at 25° C. for 4 hours. The resulting mixture was diluted with EtOAc (300 mL), washed with H2O (100 mL×5) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel column (PE/EtOAc=20/1) to give the product (2.10 g, yield 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1.[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][C:9](=[O:12])[C:8]([CH2:32][CH2:31][CH2:30][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)([C:13]([O:15][CH3:16])=[O:14])[S:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1Sc2cc(C)ccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(C)ccc2OCC1=O

Procedure:
Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (1.7 g) was reacted with 3-(4-phenylpiperazin-1-yl)propyl chloride in the same manner as in Reference Example 1 to give 0.9 g of colorless, oily methyl 7-methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8](O)[C:9]([CH3:11])=[CH2:10])[CH2:3][CH2:4][OH:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C@@H:2]([CH2:6][CH:7]=[CH:8][C:9]([CH3:11])=[CH2:10])[CH2:3][CH2:4][OH:5]
Reactant: C=C(C)C(O)CC[C@H](C)CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)C=CC[C@H](C)CCO
Yield: 80.3 %

Procedure:
(S)-3,7-dimethyl-6-hydroxy-7-octene-1-ol (I) (10.0 g, 58.1 mmol), palladium acetate (130.0 mg, 0.579 mmol), and triphenylphosphine (1.52 g, 5.795 mmol) were placed in a 50 ml three neck distillation flask provided with a thermometer and a vacuum distilling apparatus having a side arm. Butanol (20 ml) was then added to the flask and the mixture was heated for 12 hours with stirring at a reaction temperature of 115° to 120° C. and a atmospheric pressure in a stream of nitrogen. After the reaction had terminated, the flask was evacuated to remove solvent from the reaction mixture, and the resultant was distilled to obtain 7.2 g (89° to 91° C./4 mmHg) of (S)-3,7-dimethyl-5,7-octadiene-1-ol (II). The yield was 80%.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>C(O)C>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 88 %

Procedure:
A mixture of 2-nitroaniline (41.4 g) and diethyl ethoxymethylenemalonate (66 ml) was heated on a steam bath for 24 hours. The hot reaction mixture was treated with ethanol (300 ml), cooled and filtered to give diethyl (2-nitroanilino)methylenemalonate in 88% yield, mp 104-105° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13]COC)[CH:5]=[C:4]([O:17]COC)[C:3]=1[C:21](=[O:36])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]COC)=[C:26]([O:34][CH3:35])[CH:25]=1.Cl.CO.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([OH:13])[CH:5]=[C:4]([OH:17])[C:3]=1[C:21](=[O:36])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:34][CH3:35])[CH:25]=1
Reactant: COCOc1ccc(CCC(=O)c2c(OCOC)cc(OCOC)c(CCC(C)C)c2O)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCC(=O)c2c(O)cc(O)c(CCC(C)C)c2O)ccc1O
Yield: 51.4 %

Procedure:
Then, 5.0 g of 1-[2-hydroxy-4,6-bis(methoxymethoxy)-3-isopentylphenyl]-3-(3-methoxy-4-methoxymethoxyphenyl)-1-propanone was dissolved in 12.0 ml of methanol, and 37 ml of a hydrochloric acid/methanol reagent was added to the solution and the mixture was refluxed for 1 hour. The reaction liquid was neutralized with a saturated solution of sodium hydrogencarbonate and extracted with diethyl ether. The ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under a reduced pressure. The reaction mixture was subjected to the column chromatography [230-400 mesh Kieselgel 60; eluting solvent=chloroform/methanol (30/1)] to obtain 1.9 g (yield=50.9%) of 1-(2,4,6-trihydroxy-3-isopentylphenyl)-3-(4-hydroxy-3-methoxyphenyl)-1-propanone.
Reaction SMILES: N1CCCC1C(O)=O.C(=O)([O-])[O-].[K+].[K+].Br[C:16]1[N:17]=[C:18]2[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]2=[N:20][CH:21]=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40]1.C(=O)(O)[O-].[Na+]>[Cu](I)I.CCOC(C)=O.CS(C)=O>[N:39]1([C:16]2[N:17]=[C:18]3[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]3=[N:20][CH:21]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: I[Cu]I
Agent: O=C(O)C1CCCN1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ccc4ccccc43)nc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
DMSO (3 mL) was added to a mixture of copper iodide (10 mg; 0.05 mmol), d,1-proline (12 mg; 0.10 mmol), potassium carbonate (111 mg; 0.79 mmol), and 1-[2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (150 mg; 0.36 mmol). Indole (327 mg; 2.91 mmol) was added and the resulting mixture was stirred at 100° C. (oil bath) for 24 hrs. TLC analysis (25% EtOAc/hexanes) shows a new more-polar product. The reaction mixture was poured into 50 mL of saturated sodium bicarbonate solution and extracted with EtOAc (2×30 mL). The organic layers were combined, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. Chromatography (SiO2; 0-15% EtOAc in hexanes) gives 1-[2-indol-1-yl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (61%; ms=449 [M+H]) as a light brown oil. Following general procedures described in these Examples, the SEM group was removed to give 1-(2-Indol-1-yl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one (53%; MS=319 [M+H]; 1H NMR (DMSO): δ 8.83 (s), 8.64 (s), 8.48 (d, br), 8.11 (d, br), 7.69 (d), 7.31 (t), 7.21 (t), 6.83 (d) ppm; MP: 205-207° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.Cl.[NH2:26][CH2:27][C:28]#N.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:14][CH2:28][C:27]#[N:26])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 15.4 %

Procedure:
Into a flask equipped with a reflux condenser, magnetic stirrer, nitrogen inlet and heating mantle, there was added 4-(2-chloro-4-(trifluoromethyl)-phenoxy)-1,2-dinitrobenzene (5 gm, 0.014 mol), aminoacetonitrile hydrochloride (5.1 gm, 0.055 mol), anhydrous potassium carbonate (7.4 gm, 0.053 formula weight) and 50 ml of dioxane. The solution was sirred and refluxed overnight, cooled and poured into water. Following ether extraction, the organic layer was dried and evaporated to a residue. The residual material was chromatographed over silica gel using 15% acetone and 85% hexane as the eluant to yield 800 mg of the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])([CH3:7])[CH3:6]>C(#N)C.O>[C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]=1[OH:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccccc1O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1cccc([N+](=O)[O-])c1O
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
Acetyl nitrate obtained by mixing acetyl anhydride (1.35 g, 13.3 mmol) with fuming nitric acid (13.3 mmol) at 0° C. was dropped into a solution of 2-tert-butylphenol (2.00 g, 13.3 mmol) in acetonitrile (30 ml) at −20° C. followed by stirring for 5 minutes. The reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (60 g of silica gel; developing solvent, hexane:acetone=3:1) to provide 600 mg (yield 23%) of 2-tert-butyl-6-nitrophenol as yellow crystals.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.[C-:23]#[N:24].[K+].C(O)(=O)C.CC(C)=O.C(Cl)Cl>CO>[C:23]([C@@:3]1([OH:22])[C@@H:2]([CH3:1])[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3)#[N:24]
Reactant: [C-]#N
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C#N
Reaction time: 72 h

Procedure:
16β-Methylandrosta-1,4,9(11)-triene-3,17-dione (U.S. Pat. No. 3,010,958, 12.0 g) and potassium cyanide (7.909 g) are suspended in methanol (24 ml). The resulting slurry is then treated with glacial acetic acid (3.5 ml) and allowed to stir in a tightly stoppered flask at 20°-25° for 72 hr. TLC (acetone/methylene chloride, 4/96). The reaction mixture is then cooled to 0° and quenched with glacial acetic acid (4.2 ml). The solids are then collected by filtration, triturated with methanol/water (1/1, 3×10 ml) and dried by heating (60°) under reduced pressure (60 mm) to obtain the title compound, m.p. 241°-247.5°; NMR (CD2Cl2) 1.32, 1.42, 5.58, 6.08, 6.30 and 7.25 δ.
Reaction SMILES: [OH:1][C:2]1[C:9]([I:10])=[CH:8][C:7]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.[F:23][C:24]([F:33])([F:32])/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[I:10][C:9]1[CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[C:3]2[C:2]=1[O:1][CH:25]([C:24]([F:23])([F:33])[F:32])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4]2
Reactant: O=Cc1cc(OC(F)(F)F)cc(I)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Temperature: 85 °C
Yield: 69.1 %

Procedure:
The resulting product (2.5 g, 7.5 mmol) from step 1, triethylamine (2 mL) and ethyl 4,4,4-trifluorocrotonate (5.1 g, 30 mmol) were mixed in DMF (10 mL), and then the system was heated to 85° C. for reaction for 48 hrs. At the end of reaction, the reaction system was cooled to room temperature, added with water and extracted with ethyl acetate, and the organic phase was dried and evaporated in vacuum to obtain 2.5 g of the product (69%) by column chromatography.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH-](O[C:23]([CH3:25])=O)(OC(C)=O)OC(C)=O.[Na+].O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C@H:25]3[CH2:23][CH2:6][C@H:1]([NH2:7])[CH2:2][CH2:3]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N[C@H]1CC[C@H](N2CCN(c3ccccc3)CC2)CC1

Procedure:
4.1 g (25.3 mmol) of 4-dibenzylcyclohexanone was dissolved in 50 mL of dichloromethane and stirred for 12 h at RT with 7.4 g (25.3 mmol) of N-phenylpyperazine and 7.4 g (35 mmol) of NaBH(OAc)3. Then water and potassium carbonate were added, the org. phase was separated off, dried and the solvent was eliminated in vacuo. The residue was purified over a silica gel column (ethyl acetate 80/methanol 20+0.5% conc. ammonia). Yield: 1.7 g (15.8%) of cis-isomer and 0.27 (2.5%) of trans-isomer.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C=O)C.O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([OH:10])[CH:12]=1)[CH3:43]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIPEA (375 μL, 2.17 mmol) was added drop wise to 3-hydroxy benzoic acid (100 mg, 0.72 mmol) in DMF (4 mL). EDCI (208 mg, 1.09 mmol) and HOBT (117 mg, 0.87 mmol) were added consecutively and after 15 mins, glycine ethyl ester HCl (120 mg, 0.87 mmoles) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford (3-Hydroxy-benzoyl amino)-acetic acid ethyl ester in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].OS(O)(=O)=O.[BrH:15].N(C(C)(C)C#N)=NC(C)(C)C#N.OO>ClC1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Br:1])=[C:3]([CH:4]=[CH:5][CH:6]=1)[CH2:9][Br:15]
Reactant: Cc1cccc(Cl)c1Br
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Clc1cccc(CBr)c1Br

Procedure:
267.7 g of 2-bromo-3-chlorotoluene, 530 g of chlorobenzene, 2.5 g of conc. H2SO4, 257.9 g of 47% strength hydrobromic acid and 14 g of 2,2'-azobis(2-methylpropionitrile) were mixed at 63° C. in a 2 l stirred apparatus. 332.3 g of a 10% strength aqueous hydrogen peroxide solution were added dropwise over the course of one hour and 25 minutes, and then the mixture was stirred at 63° C. for 30 minutes. GC analysis of the org. phase:
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][CH2:7][C@@H:8]3[CH2:13][S:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:10][C@@:9]32[CH3:24])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].CN[C@@H]1CCCC[C@H]1NC.[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[N:25]([C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][CH2:7][C@@H:8]3[CH2:13][S:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:10][C@@:9]32[CH3:24])=[CH:4][CH:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(Br)ccc3CC[C@@H]2CS1
Agent: [Cu+2]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N=[N+]=[N-])ccc3CC[C@@H]2CS1
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of tert-butyl rel-((4aS,10bS)-9-bromo-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate from preparation C (300 mg, 0.729 mmol) in ethanol (3.6 mL) was added sodium azide (228 mg, 3.51 mmol), trans-1,2-bis(methylamino)cyclohexane (55 mg, 0.387 mmol), 0.66 M solution of aqueous L-ascorbic acid sodium salt (0.780 mL, 0.515 mmol) and water (0.70 mL) and the mixture was purged with nitrogen for 10 min. A 0.33 M solution of aqueous copper(II) sulfate pentahydrate (0.780 mL, 0.257 mmol) was added and the reaction was heated to 80° C. for 12 min. The reaction was poured into water and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (2:1 hexanes/EtOAc) to afford tert-butyl rel-((4aS,10bS)-9-azido-10b-methyl-4a,5,6,10b-tetrahydro-4H-naphtho[1,2-d][1,3]thiazin-2-yl)carbamate (190 mg, 0.509 mmol, 70% yield) as a clear viscous oil. LCMS (M+Na)+=396.1. 1H NMR (500 MHz, chloroform-d) δ 7.11 (br. s., 1H), 7.09 (d, J=8.2 Hz, 1H), 6.89 (dd, J=8.2, 2.1 Hz, 1H), 3.03 (dd, J=12.9, 3.6 Hz, 1H), 2.94-2.79 (m, 3H), 2.27 (br. s., 1H), 2.21-2.07 (m, 1H), 1.99 (dq, J=13.8, 6.7 Hz, 1H), 1.62 (s, 3H), 1.48 (s, 9H).