Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH:21]1([O:1][C:2]2[CH:9]=[CH:8][C:7]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=Cc1cc(-n2cnnn2)ccc1O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-n2cnnn2)ccc1OC1CCCC1

Procedure:
A mixture of 2-hydroxy-5tetrazol-1-yl-benzaldehyde (500 mg) and potassium carbonate (431 mg) in dimethylformamide (5 ml) at 20° was treated with cyclopentyl bromide (0.33 ml). After 24 h water (20 ml) was added and the mixture extracted with ethyl acetate (2×25 ml). The organics were washed with water (25 ml) and brine (25 ml) and dried (Na2SO4). Evaporation gave a yellow solid which was purified by FCC (ethyl acetate/cyclohexane (2:1)) to give the title compound, as a yellow solid (334 mg).
Reaction SMILES: CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)N[C:21](=[O:22])[CH:20]([CH2:127][C:128]2[CH:133]=[CH:132][C:131](O)=[CH:130][CH:129]=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C.IC1C=CC=CC=1C(OC(C)(C)C)=O.Br[C:160]1[CH:165]=[CH:164][C:163]([F:166])=[CH:162][N:161]=1>>[F:166][C:163]1[CH:164]=[CH:165][C:160]([C:131]2[CH:130]=[CH:129][C:128]([CH2:127][CH2:20][CH:21]=[O:22])=[CH:133][CH:132]=2)=[N:161][CH:162]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Agent: CC(C)(C)OC(=O)c1ccccc1I
Product: O=CCCc1ccc(-c2ccc(F)cn2)cc1

Procedure:
The title compound was prepared following the procedure described for intermediate 1 substituting tert-butyl 2-iodobenzoate with 2-bromo-5-fluropyridine. 1H NMR (500 MHz, CDCl3) δ 9.83 (s, 1H), 8.52 (d, J=2.9 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.67-7.70 (m, 1H), 7.42-7.46 (m, 1H), 7.29 (d, J=8.2 Hz, 2H), 3.0 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[C:6]2[NH:10][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[N:8][C:7]=2[CH:27]=1.[CH3:38][C:39]([CH3:41])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[CH:39]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:5]2[C:6]3[NH:10][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][CH2:12]4)=[N:8][C:7]=3[CH:27]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=2)=[CH:29][CH:30]=1)([CH3:41])[CH3:38]
Reactant: CC(C)=O
Reactant: NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)NCc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncccc5C(F)(F)F)CC4)[nH]c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-(5-(trifluoromethyl)-2-{4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-1H-benzimidazol-7-yl)benzylamine (172 mg, 0.33 mmol, Example 75) and acetone (1 mL) in chloroform (5 mL) were added NaBH(OAc)3 (211 mg, 1 mmol) and one drop of acetic acid. The mixture was stirred at room temperature for 2 h, diluted with dichloromethane (30 mL), washed with satd aq. NaHCO3 solution (25 mL), dried over Na2SO4, and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 5% MeOH in dichloromethane to give the title compound as white amorphous solid. MS (ESI, pos. ion) m/z: 563 (M+1), (ESI, neg. ion)
Reaction SMILES: [OH2:1].[C:2]([C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:3].Cl.[NH2:10]O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:3][C:2](=[N:10][OH:1])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O
Reactant: NO
Reactant: CCOC(=O)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(N)=NO
Temperature: 25 °C
Yield: 91 %

Procedure:
Water (600 ml) is added dropwise over a period of two hours to a vigorously stirred, room temperature mixture of ethyl cyanoformate (99 g, 1 mol), hydroxylamine hydrochloride (105 g, 1.5 mol ) and sodium carbonate (82 g, 0.77 mol ) in ethanol (1 L.) The resulting solution is stirred until the starting material has been consumed. When the reaction is complete, most of the solvent is removed in vacuo and the resulting residue is extracted with methylene chloride (3×200 ml.) The combined organic extracts are washed with brine (250 ml), dried (Na2SO4), filtered and concentrated to afford 120.1 g (91%) of compound 2a as a white solid. Further purification can be achieved by crystallization from chloroform and hexanes. 1H NMR (CDCl3): δ9.15 (br s, OH), 5.12 (br s, 2H), 4.32 (q, 2H), 1.42 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ161.4, 144.4, 62.8, 14.3.
Reaction SMILES: [I-].C[S+](C)C.[CH3:6][Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:16][CH2:17][C@@H:18]1[CH2:20][O:19]1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CN1CCCC1=O>[F:16][CH2:17][C@@H:18]([O:19][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:20]=[CH2:6]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: FC[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[S+](C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C=C[C@@H](CF)OCC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Into a different flask, trimethylsulfonium iodide (181.35 g, 888.65 mmol) was dissolved in THF. The solution was cooled to −30° C. Lithium hexamethyldisilazide (888.65 mL, 1 M solution in THF, 888.65 mmol) was added over 25 mins. The internal temperature went from −30° C. to −26° C. upon the addition. The reaction was stirred at −30° C. for 30 mins. To this solution was added the (S)-2-(fluoromethyl)oxirane solution (that was prepared in the previous flask). The addition was done over 5 mins at −30° C. The reaction was then allowed to warm up to RT and stirred for 3 h. It was then cooled to 3° C. (internal temperature) using an ice bath and 1-methyl-2-pyrrolidinone (100 mL) was added. The internal temperature rose to 8° C. tert-Butyl bromoacetate (131.22 mL, 888.65 mmol) in 1-methyl-2-pyrrolidinone (100 mL) was added dropwise using a dropping funnel and ensuring the temperature remained between 17-20° C. The reaction was stirred in the ice bath for 10 mins until the temperature went to 5° C. The ice bath was removed and it was stirred at RT overnight. Water (2 L) was poured into the reaction mixture and followed by Et2O (1 L). After stirring for 10 mins the two layers were separated and the aqueous layer was extracted with Et2O (4×500 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by silica gel column chromatography using hexanes initially and then 5% EtOAc in hexanes to obtain the title compound as a yellow liquid (57 g, 63%).
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:18][S:19][CH2:20][C:21]([NH2:23])=[S:22]>C1CCCCC1.C(OCC)(=O)C>[CH3:18][S:19][CH2:20][C:21]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH3:16])[N:23]=1
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CSCC(N)=S
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CSC)sc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
A mixture of 5 g of 2-chloro-1-(4-nitrophenyl)-hexan-3-one (0.02 mol) and 2.6 g of (methylthio)thioacetamide (0.022 mol) is heated at 60° C. for 24 h. The reaction is followed by TLC (7/3 cyclohexane/ethyl acetate). The reaction medium is then treated according to the process of Example 45 to give 5.6 g of 2-methylthiomethyl-5-(4-nitrobenzyl)-4-propylthiazole in the form of an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[F:20])(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(F)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4-difluorobenzene-1-sulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C.[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>[CH3:7][N:6]1[C@H:5]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:11][C:2]([C:2]4[CH:11]=[CH:10][CH:9]=[C:8]5[C:3]=4[CH:4]=[CH:5][N:6]=[CH:7]5)=[CH:3][C:19]=3[CH2:20][CH2:4]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: Brc1cccc2cnccc12
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5cnccc45)cc3CC[C@@H]12
Yield: 42 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 5-bromoisoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 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 (5% methanol/ethyl acetate eluent) to give 98 mg (42%) of the title compound as an amorphous solid. mp 182°-184°. FDMS: m/e=356. α[D]589 =+57.25 (c=0.49, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:10]=[N:11][NH:12][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nn[nH]n2)cc1
Yield: 76 %

Procedure:
4-Bromobenzonitrile (20 g, 110 mmol), sodium azide (7.9 g, 121 mmol) and NH4Cl (6.5 g, 121 mmol) in DMF (340 mL) were heated at 90° C. under argon. After 2 days the reaction mixture was concentrated and then diluted with water (300 mL). After adding enough 1M NaOH to render the mixture basic (litmus paper) it was washed with ether (4×25 mL). The aqueous portion was acidified to pH 3 with 1N HCl, the precipitated product was collected by suction filtration and then washed with water. The crude product was recrystallized from ethanol to give crystalline 5-(4-bromophenyl)-2H-tetrazole (19.2 g, 83.6 mmol) in 76% yield, mp. 271°-273° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:35]=[CH:34][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:36](Br)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C=O>[CH:14]([O:15][CH:16]([CH3:17])[CH3:21])([CH3:34])[CH3:13].[C:3]([O:7][C:8]([N:10]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:11]1[CH:35]=[CH:34][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:28])[CH3:26])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 192.8 %

Procedure:
To a suspension of sodium hydride (1.26 g 55% w/w) in anhydrous N,N-dimethylformamide (100 ml) was added t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarbamate (12.1 g). The mixture was stirred at room temperature for several minutes. To this mixture was added hexyl bromide (6.5 g) in an ice bath and the mixture was stirred for 30 minutes and then at room temperature for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using toluene:diisopropyl ether=100:7 as the eluant to afford the desired compound (13.8 g). Rf=0.32: thin layer chromatography on a silica gel plate using toluene/diisopropyl ether=100:7 as the eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:10]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N+:5]([O-:10])[CH:6]=[CH:7][CH:8]=1
Reactant: OO
Reactant: COc1cccnc1C
Solvent: CC(=O)O
Product: COc1ccc[n+]([O-])c1C
Reaction time: 3 h
Yield: 60 %

Procedure:
15.3 g (0.124 mole) of 3-methoxy-2-methylpyridine are dissolved in 100 ml of glacial acetic acid, and 40 ml of 30% strength hydrogen peroxide are added in 4 portions at 80° C. in the course of 6 hours. The mixture is stirred for a further three hours and then concentrated in vacuo (1.5 kPa), and two 50 ml portions of acetic acid are added, the mixture being concentrated completely after each addition. Following negative detection of per-compounds, the mixture is distilled in a bulb tube oven. The fraction which distills at 120° C. (1.5 Pa) is extracted by stirring in a little diethyl ether and the solid is filtered off and dried. 12 g (60% of theory) of 3-methoxy-2-methylpyridine 1-oxide are obtained in the form of colorless crystals of m.p. 72°-78° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[C:17]1([C:16]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and TEA (0.74 mL, 5.3 mmol) in CH2Cl2 was added benzoyl chloride (0.61 mL, 5.26 mmol) dropwise and the mixture was allowed to stir overnight. The reaction mixture was diluted with water and the resulting solid was collected by vacuum filtration. The solid was allowed to air dry, to yield compound 25 as a white solid. Synthesis of phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26):
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])C.[CH3:22][O:23][C:24](=[O:34])[C@@H:25]([NH2:33])[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:33][C@H:25]([C:24]([O:23][CH3:22])=[O:34])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5]
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1Oc2c(OC)ccc(OC)c2C=C1CN[C@@H](CC1CCCCC1)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.4 %

Procedure:
To a solution of 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (2.0 g, 6.48 mmol) in methanol (40 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (1.51 g, 6.84 mmol) and N,N′-diisopropylethylamine (1.76 mL, 13.68 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.86 g, 13.68 mmol) and acetic acid (0.78 mL, 13.68 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 3-[((S)-2-cyclohexyl-1-methoxycarbonyl-ethylamino)-methyl]-5,8-dimethoxy-2H-chromene-2-carboxylic acid methyl ester (1.2 g, 37.5%) as an oil.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[CH3:10][OH:11].C[O-].[Na+]>O>[F:8][C:7]1[C:2]([O:11][CH3:10])=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: CO
Reactant: Fc1ccc(F)c(F)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(F)ccc1F
Reaction time: 0.17 h
Yield: 69 %

Procedure:
step 1—To a flask containing 2,3,6-trifluoropyridine (2 g, 15 mmol) was added MeOH (5 mL) followed by methanolic NaOMe (5 mL, 25% NaOMe in MeOH). An exothermic reaction occurred and some solid formed. The reaction was stirred for 10 min and diluted with H2O. The solid was filtered and washed with H2O. The solid was dissolved in EtOAc, washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 1.5 g (69%) of 3,6-difluoro-2-methoxy-pyridine (140). The recovered material was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[CH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OCC)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)c(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)c(C=C(C)C)cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
To a solution of 5-bromo-4-methyl-pyridine-2-carboxylic acid ethyl ester (4.03 g, 16.5 mmol) in DME (43 mL), 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (5.36 g, 16.5 mmol) followed by 2 N aq. K2CO3-solution (16 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (343 mg, 0.297 mmol) is added. The mixture is stirred at 80° C. for 6 h before it is cooled to rt, diluted with diethyl ether (50 mL), washed with sat. aq. NaHCO3-solution (3×30 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 4-methyl-5-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (1.33 g) as a yellow oil; LC-MS: tR=0.87 min, [M+1]+=220.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([O-])([O-])OCC.[N-:22]=[N+:23]=[N-:24].[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:15]2[CH:16]=[N:24][N:23]=[N:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CCOC([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: c1ccc(COc2cccc(-n3cnnn3)c2)cc1
Reaction time: 4 h
Yield: 34.2 %

Procedure:
To a solution of 3-Benzyloxy-phenylamine (1.50 grams, 7.53 mmole) and acetic acid (15 ml) at 70° C. was added a solution of ethyl orthoformate (1.116 g, 7.53 mmole) in acetic acid (4 ml) and stirred for 4 hours. To the solution was added sodium azide (1.468 g, 22.6 mmole) in two portions and stirred for 20 hours at 70° C. The mixture was extracted with ethyl acetate. The combined extracts were washed with saturated sodium hydrogencarbonate and brine, dried over Na2SO4, filtered, and concentrated. The product was purified via flash chromatography on silica using 3/1 hexane/ethyl acetate as eluent to give white crystals (0.650 g). M.P. 85-86° C.; MW 252.25; MS (m/e) 252.8 (M+).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: C[n+]1ncc(N)cc1Cl
Reactant: Oc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: CC#N
Product: C[n+]1ncc(N)cc1Oc1ccccc1

Procedure:
12.2 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 150 parts of acetonitrile is stirred with 5 parts of phenol and 4 parts of pyridine for 4 hours at 80° C. The reaction mixture is filtered and the filtrate is concentrated at subatmospheric pressure. About 200 parts of water is added. 5.5 parts (36.6% of theory) of 1-methyl-4-amino-6-phenoxypyridazinium perchlorate is obtained; C11H12O5N3Cl, melting point 182° to 184° C after having been recrystallized from water.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].C1(C)C=CC=CC=1.[CH3:14][C:15]([Si:20]([CH3:43])([CH3:42])[O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C:24](=[CH:25][CH:26]=[C:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30][C:31]2=O)[CH2:23]1)([CH3:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O>[CH3:14][C:15]([Si:20]([O:21][C@H:22]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C:24](=[CH:25][CH:26]=[C:27]3[C@@H:36]2[CH2:35][CH2:34][C@@:32]2([CH3:33])[C@H:28]3[CH2:29][CH2:30]/[C:31]/2=[CH:1]/[CH3:2])[CH2:23]1)([CH3:43])[CH3:42])([CH3:19])[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C/C=C1/CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 240.2 g (647 mmol) (ethyl)triphenylphosphonium bromide, 72.5 g (647 mmol) potassium t-butoxide, and toluene (1 L) was stirred at room temperature for 1 hr. Then, 185 g (430 mmol) (3β)-3-[[(1,1,2-trimethylpropyl)dimethylsilyl]-oxy]androsta-5,7-dien-17-one was added with the aid of 50 mL of toluene. The temperature was kept below 25° C. by water cooling. After stirring at room temperature overnight, the reaction was quenched with 24.5 mL (430 mmol) of acetic acid. After stirring for 1 hr, the solid was removed by filtration and washed with 600 mL of toluene. The combined filtrate and washes were concentrated. Then 200 mL of methanol was added and the mixture was concentrated again. The residue was dissolved in a mixture of 650 mL methanol, 65 mL water and 650 mL hexane. The methanol/water layer was back-extracted with 325 mL of hexane. The combined hexane layers were concentrated. Then, 200 mL of methanol was added and the mixture was concentrated again. The resulting solid was suspended in 800 mL of methanol containing 8 mL of triethylamine, and the suspension was refluxed for 30 minutes. After cooling in a refrigerator overnight, the precipitate was filtered, washed with 300 mL of cold methanol, and dried by suction for 4 hr. Further drying at 50° C. under high vacuum afforded, 178.1 g (93.7% yield) of (3β,17Z)-(1,1,2-trimethylpropyl)(pregna-5,7,17(20)-trien-3-yloxy)dimethylsilane as a yellow solid: mp 94°-97° C. [α]D -62.8° (c 0.94, ethanol); Anal. Calcd for C29H48OSi: C, 79.02; H, 10.98; Si, 6.37. Found C, 78.74; H, 11.23; Si, 6.50.