Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:9][SiH:10]([CH3:12])[Cl:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCCCCCC
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](C)(C)Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
123 g (1.1 mol) 1 -octene and 100 microliters of a 2% toluene solution of chloroplatinic acid were placed in a 500-mL four-neck flask equipped with a stirrer, thermometer, addition funnel, and condenser and were heated to 70° C. After the temperature had been raised, the heating mantle was removed and 94.5 g (1 mol) dimethylchlorosilane was added dropwise from the addition funnel. Heat generation was observed immediately, and the dropwise addition was carried out gradually so as to avoid having the temperature of the reaction solution exceed 80° C. After the completion of this addition, the reaction was continued for 30 minutes at 80° C. Gas chromatographic analysis of the resulting reaction solution gave 88% octyldimethylchlorosilane. The reaction solution was cooled to room temperature and 200 g toluene was introduced. The addition funnel was then replaced with a Teflon tube and ammonia was bubbled in until the pH of the reaction solution reached 10. The ammonium chloride product was removed by filtration, and the filtrate was then distillatively purified at 160° C./0.5 mmHg to obtain the following disilazane in a purity of 98 weight %.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].O=P(Cl)(Cl)Cl.CN(C1C=CC=CC=1)[CH:19]=[O:20]>>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([CH3:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH:19]=[O:20]
Reactant: CN(C=O)c1ccccc1
Reactant: COc1ccc(OC)c(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C=O)c(OC)cc1C

Procedure:
To a solution of 2,5-dimethoxytoluene (4.66 g, 30.6 mmol) in 60 mL of N-methyl-N-phenyl-formamide was added at 0° C. POCl3 (8.41 mL, 3 eq.), and the mixture was heated for 60 Min. to 80° C. After cooling, the reaction mixture was poured onto crashed ice, twofold extracted with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 4.153 g of the title compound as off-white solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:8]=[CH:7][O:6][CH:5]=1.[Li]CCCC.CCCCCC.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>C1COCC1>[O:6]1[CH:7]=[CH:8][C:4]([C:3]#[C:2][Si:22]([CH3:24])([CH3:23])[CH3:21])=[CH:5]1
Reactant: BrC(Br)=Cc1ccoc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)C#Cc1ccoc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 141 %

Procedure:
To a stirred and cooled (−78° C.) solution of the dibromofuran 10 (2.0 g, 7.9 mmol) in THF (20 mL) was added 1.6 M n-BuLi in hexane (10.2 mL, 16.3 mmol) over 3 min. After 1 h the cooling bath bath was removed and the mixture allowed to warm to r.t. Following a further 1.5 h the mixture was cooled back to −78° C. and then TMSCl (3.0 mL, 23.8 mmol) was added dropwise. The mixture was allowed to gradually warm up to r.t. After 19 h the mixture was poured into ice-cold Et2O-saturated aqueous NaHCO3 solution. The organic layer was separated and the aqueous layer extracted with Et2O (2×). The combined organic solutions were dried (MgSO4), filtered and concentrated to afford the crude acetylene 11 (1.83 g) as a yellow oil. This material was used in the next step without purification. 1H NMR (400 MHz; CDCl3) inter alia δ 0.23 (s, 9H), 6.44 (m, 1H), 7.34(m, 1H) and 7.63 (m, 1H).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=2[Cl:27])[CH2:8][CH2:7][CH2:6]1)(O)=[O:2].[CH:29]([NH2:32])([CH3:31])[CH3:30].P(C#N)(OCC)(OCC)=O.C(OCC)(=O)C>CN(C)C=O>[CH:29]([NH:32][C:1]([CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][CH3:26])=[CH:19][C:18]=2[Cl:27])[CH2:8][CH2:7][CH2:6]1)=[O:2])([CH3:31])[CH3:30]
Reactant: CCCNc1ccc(C(=O)N2CCCC(CC(=O)O)c3ccccc32)c(Cl)c1
Reactant: CC(C)N
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNc1ccc(C(=O)N2CCCC(CC(=O)NC(C)C)c3ccccc32)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of the above product, 5-carboxymethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (800 mg) and isopropylamine (1.0 ml) in dimethylformamide (20 ml) is added dropwise diethyl cyanophosphate (391 mg) at room temperature. The mixture is stirred overnight, and thereto is added ethyl acetate. The mixture is washed with water, dried, concentrated, and purified by silica gel column chromatography (solvent; dichloromethane:methanol=50:1), and further crystallized from diethyl ether to give 5-isopropylaminocarbonylmethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (840 mg).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([NH2:13])(=[O:12])=[O:11])[C:4]=2[CH2:3][S:2]1(=O)=O.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](=O)[O:32]C)[N:23]=1.Cl>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:13][S:10]([C:9]2[C:4]3[CH2:3][S:2][CH2:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)(=[O:12])=[O:11])=[O:32])[N:25]=1
Reactant: NS(=O)(=O)c1cccc2c1CS(=O)(=O)C2
Reactant: COC(=O)Nc1nc(OC)cc(OC)n1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cccc3c2CSC3)n1
Temperature: 25 °C
Yield: 26.1 %

Procedure:
A suspension of 0.74 g of the sulfonamide prepared in Example 13 in 50 ml of methylene chloride was cooled to 10° to 15° under nitrogen, and 1.7 ml of a 2M solution of trimethylaluminum in toluene was added slowly. The suspension was allowed to warm to room temperature, 0.67 g of methyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate was added, and the reaction mixture was heated at reflux overnight. The turbid solution was cooled to 0°-5° and 50 ml of 5% hydrochloric acid was added dropwise. The two-phase suspension was allowed to warm to ambient temperature, then filtered. The solid was washed with 1-chlorobutane and dried giving 0.31 g of 1,3-dihydro-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzo[c]thiophene-4-sulfonamide, 2,2-dioxide, m.p. 170°-173°(d).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1N1CCCCC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of piperidine gives 700 mg of the desired product: M+ =491.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[N:12].[NH2:14][OH:15]>CCO>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11](=[N:14][OH:15])[NH2:12]
Reactant: CN(C)CCOCCOCCC#N
Reactant: NO
Solvent: CCO
Product: CN(C)CCOCCOCCC(N)=NO
Yield: 90.2 %

Procedure:
A solution of 3-(2-(2-(dimethylamino)ethoxy)ethoxy)propanenitrile (0.5 g, 2.68 mmol) and NH2OH (50% in water, 0.25 cm3, 4 mmol) in EtOH (10 cm3) were stirred at 80° C. for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line for several hours to give give 3-(2-(2-(dimethylamino)ethoxy)ethoxy)-N′-hydroxypropanimidamide (0.53 g, 90.1%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cl

Procedure:
The title compound was prepared by reacting 2-chloro-phenol, with ethyl 2-bromoacetate and K2CO3 in DMF. Yield, 97%, colourless oil; 1H NMR (CDCl3): 1.29 (3H, t, J=6.3, CH2CH3), 4.29 (2H, q, J=6.3, CH2CH3), 4.72 (2H, s, OCH2), 6.76 (1H, d, J=8.2, H-6), 6.95 (1H, m, H-4), 7.20 (1H, m, H-5), 7.40 (1H, dd, J=8.2, H-3).
Reaction SMILES: [CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11](O)=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH:1]12[CH2:14][CH:7]([CH:8]3[CH:10]1[CH:9]3[C:11]([Cl:18])=[O:12])[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1C2C3CC(C4CCCC43)C12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1C2C3CC(C4CCCC43)C12
Reaction time: 2 h

Procedure:
To a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carboxylic acid (0.43 g, 2.2 mmol, Bennani, Y. L., et al., US2004077617) in dichloromethane (11 mL) was added oxalyl chloride 0.21 mL, 2.4 mmol) and a catalytic amount of dimethylformamide (2 drops). The mixture was stirred for 2 hours and then concentrated under reduced pressure to afford tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride. To a suspension of the product of Example 46A (0.30 g, 1.1 mmol) and triethylamine (0.46 mL, 3.3 mmol) in tetrahydrofuran (5 mL) was added a solution of tetracyclo[5.3.1.02,6.08,10]undecane-9-carbonyl chloride (0.23 g, 1.2 mmol) in tetrahydrofuran (1 mL). The mixture was heated at reflux for 14 hours, then cooled to room temperature and diluted with water and CH2Cl2. The layers were separated and the organic extract was washed with water and brine, dried (Na2SO4), and concentrated. Purification by column chromatography (SiO2, 10-35% ethyl acetate/hexanes gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.94 (d, J=10.5 Hz, 1H), 1.22 (d, J=11.9 Hz, 1H), 1.45-1.76 (m, 6H), 1.87-1.98 (m, 2H), 2.17 (s, 3H), 2.20 (s, 3H), 2.32 (s, 2H), 2.35-2.43 (m, 3H), 3.30 (s, 3H), 3.70 (t, J=5.3 Hz, 2H), 4.20-4.33 (m, 2H); MS (DCI/NH3) m/z 361 (M+H)+. Anal. Calculated for C20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found: C, 66.49; H, 7.91; N, 7.53.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=CN(C)C)[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[O:2])[N:12]([C:23]1[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=1)[C:11]2=[O:30]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ncccc1-n1c(C=CN(C)C)nc2ccc(F)cc2c1=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Yield: 83.3 %

Procedure:
To a well stirred mixture of sodium periodate (1.76 g, 8.26 mmol) in pH 7 buffer (10 mL) and tetrahydrofuran (15 mL) was added 6-fluoro-2-(2-dimethylamino-vinyl)-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one (0.69 g, 2.12 mmol) all at once. The mixture warmed slightly to the touch and was stirred for 1 hour at ambient temperature. The reaction was concentrated at reduced pressure and the residue treated with a 1:2 mixture of water and chloroform. The tan solid was collected, washed well with water and chloroform and dried under a stream of nitrogen to afford 0.50 g (80%) of 6-fluoro-3,4-dihydro-3-(2-methyl-pyridin-3-yl)-quinazolin-4-one-2-carboxaldehyde as a 1:1 mixture of free aldehyde and hydrate which had: mp 175-177° C.; 1H NMR δ 9.46 (s, 0.5 H) [CHO], 8.53 (br s, 1 H), 8.10-8.07 (s, 0.5 H), 7.94-7.70 (m, 3.5 H), 7.39-7.32 (m, 1 H), 6.59 (br s, 0.5 H) [hydrate OH], 6.47 (br s, 0.5 H) [hydrate OH], 5.17 (s, 0.5 H) [hydrate methine CH], 2.20 (s, 3 H); APCI MS m/z=284.1 (P+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][C:18]([CH3:20])([CH3:19])[C:12]2=[N:11][C:10]=1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:55][CH2:56][C:57]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][C:58]=1[C:59]([NH:61][CH3:62])=[O:60]>CN(C=O)C.CN(C)C1C=CN=CC=1>[F:67][C:64]1[CH:65]=[CH:66][C:57]([CH2:56][NH:55][C:21]([C:10]2[N:11]=[C:12]3[C:18]([CH3:19])([CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:22])=[C:58]([C:59](=[O:60])[NH:61][CH3:62])[CH:63]=1
Reactant: CNC(=O)c1cc(F)ccc1CN
Reactant: CC1(C)CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC2(C)C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
Intermediate 6, 3-(benzyloxy)-8,8-dimethyl-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine-2-carboxylic acid, (79 mg, 0.25 mmol) was placed together with O-(7-azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HATU, (114 mg, 0.3 mmol) in 2 mL DMF under N2 and stirred for 20 min. 4-(Dimethylamino)pyridine, DMAP, (100 mg, 0.8 mmol) and intermediate 3, 2-aminomethyl-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (89 mg, 0.3 mmol) in 1 mL DMF were added and stirring continued for 20 min. The reaction mixture was concentrated, the residue dissolved in CH2Cl2 and washed with H2O. The CH2Cl2 layer was separated, dried (MgSO4), filtered and concentrated to give 118 mg of a the title compound as a solid (Yield=95%). 1H NMR (300 MHz, CDCl3) δ ppm: 8.31–8.46 (1 H, m) 7.24–7.46 (5 H, m) 6.95–7.15 (3 H, m) 6.88 (1 H, s) 5.23 (2 H, s) 4.48 (2 H, d, J=6.6 Hz) 3.95–4.10 (2 H, m) 2.93 (3 H, t, J=5.1 Hz) 2.00–2.16 (2 H, m) 1.34 (6 H, s); LC/MS m/z 479 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][C:19]([N:28]([CH3:30])[CH3:29])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:12])[NH:14][CH2:15][CH:16]2[CH2:17][CH2:18][C:19]([N:28]([CH3:30])[CH3:29])([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The chloroformic acid 4-nitrophenyl ester (913.5 mg, 4.53 mmole) dissolved in abs. DCM (15 ml) was slowly added dropwise while cooling in ice water to a solution of (4-aminomethyl-1-phenylcyclohexyl)-dimethylamine (1 g, 4.3 mmole) in abs. DCM (15 ml) and pyridine (766 μl, 9.49 mmole). The reaction mixture was then stirred for 20 hours at RT. The red reaction mixture was worked up by washing with water (3×10 ml), with 1M HCl (3×10 ml) and with 1M NaOH (2×10 ml). The organic phase was dried with Na2SO4 and then concentrated by evaporation. The residue was a mixture of the diastereoisomers of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid 4-nitrophenyl ester (1.25 g, reddish-brown oil, 73%).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[Br:11]Br>CC(O)=O.O>[Br:11][C:2]1[S:1][C:5]2[C:6](=[O:10])[NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: O=C1NCCc2ccsc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1NCCc2cc(Br)sc21
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
To a 0° C. solution of 5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (820 mg, 5.36 mmol) in HOAc (7 mL) and (5 mL) water was added bromine (303 μL, 5.9 mmol) and the reaction was stirred 1.5 h. The reaction was diluted in water (30 mL) and the aqueous mixture was extracted with EtOAc (2×50 mL). The combined organics were washed with 5% aq. Na2SO3 (40 mL), sat. aq. NaHCO3 (40 mL), and brine (40 mL). The organic was dried over Na2SO4, then filtered and concentrated. After purification by flash chromatography over silica gel (50-100% EtOAc/hexane eluent), 2-bromo-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (906 mg, 73% yield) was isolated as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.10 (s, 1H), 3.55 (t, J=7.0 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H); MS (EI) m/z=233.1 [M+1]+.
Reaction SMILES: C[Si](C)(C)CCOCN1C=C([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][N:13]=2)C=N1.[O:21](S(C(F)(F)F)(=O)=O)[S:22]([C:25]([F:28])([F:27])[F:26])(=O)=[O:23]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[S:22]([O:18][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][CH:17]=1)(=[O:23])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)CCOCn1cc(-c2cc(O)ccn2)cn1
Solvent: ClCCl
Product: O=S(=O)(Oc1ccncc1)C(F)(F)F
Reaction time: 1 h
Yield: 123.3 %

Procedure:
To solution of 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-ol (0.67 g, 2 mmol) in DCM was added TEA (0.69 g, 7 mmol) and the mixture was stirred at OC, (Tf)2O (0.843 g, 3 mmol) was added slowly. The resulting reaction mixture was steered at r.t. for one hour. Solvent was removed under vacuo. And the residue was purified by silicone gel column to afford 2414(2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-4-yl trifluoromethanesulfonate (0.56 g, 58%) LCMS-ESI+ (m/z): [M+H]+ calcd. for C26H30N5O3: 424.48; found: 424.05.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].Cl.[C:25]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)(=[NH:27])[NH2:26].C([O-])(O)=O.[Na+].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:26]=[C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[NH:27][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: N=C(N)c1ccncc1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c[nH]c2c1-c1nc(-c3ccncc3)[nH]c1CCC2
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole 1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(1.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether. The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR (CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H) Step 2: A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(467 mg, 1.2 mmol), 4-Amidinopyridine hydrochloride(953 mg, 6.1 mmol), and NaHCO3(813 mg, 9.7 mmol) in dioxane(20 mL) is refluxed for 20 h. After cooling to RT, MeOH(5 mL) is added and the mixture is filtered. The filtrate is concentrated in vacuo and the brown residue is purified by flash chromatography on silica gel (10% MeOH/CH2Cl2) to yield 197 mg of 2-Pyridin-4-yl-4,5,6,7-tetrahydro-3H-1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow solid (53%). 1H NMR (CDCl3) 2.06 (quint, 2H), 2.98 (t, 2H), 3.04 (t, 2H), 3.91 (s, 1H), 7.46 (s, 1H), 7.76 (d, 2H), 8.28 (br s, 1H)8.56 (d, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.N#N.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ncc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: N#N
Solvent: CC#N
Product: COc1ccc2c(Cl)nncc2c1
Yield: 98.2 %

Procedure:
A suspension of 6-methoxy-2H-phthalazin-1-one (6.4 g, 36.3 mmoles), prepared as described in example 3, in acetonitrile (65 ml) under stirring and dry N2 at room temperature, was dropwise added with phosphorous oxychloride (6.8 ml, 73 mmoles), then the mixture was refluxed. After 3 hours the mixture was concentrated, taken up in water, neutralised with NaHCO3 and extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and concentrated to give 6.94 g of the title compound (yield: 98.3%). m.p.: 181-183° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])#[N:10]
Reactant: C=CC#N
Reactant: NCCCCN
Solvent: CO
Product: N#CCCNCCCCN
Reaction time: 12 h
Yield: 79.8 %

Procedure:
To a solution of 1,4-diaminobutane (8.6 g, 97.6 mmol) in methanol (3.0 ml) was added a solution of acrylonitrile (6.2 g, 116.8 mmol) in methanol (3.0 ml) at 0° C., and the mixture was stirred for 12 hours. Evaporation of the solvent in vacuo afforded N-(2'-cyanoethyl)-1,4-diaminobutane as a colorless oil (11.0 g, 80%). 1H NMR (400 MHz, CDCl3) δ: 1.45 (4H, br, --CH2 CH2 --), 2.46 (2H, t), 2.58 (2H, t), 2.62 (2H, t) and 2.84 (2H, t).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a solution of benzyl alcohol (1.04 mL, 10.0 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (40 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is rotary evaporated, and the residue is vacuum distilled at 110° C. to give 1.81 g of the product 390. 1H NMR (CDCl3) δ 7.4-7.26 (m, 5H), 4.65 (s, 2H), 4.23 (q, 2H), 4.10 (s, 2H), 1.30 (t, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28](C(OC(C)(C)C)=O)[C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)[CH2:16][O:17][C:19]1[CH:20]=[C:21]2[NH:28][C:27]([CH3:37])([CH3:36])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2ccnc(F)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4ccnc(F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-fluoropyridin-4-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1.[CH3:29][CH:30]([CH3:34])[CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[CH3:2][N:3]([CH3:28])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][CH2:14][N:13]([CH2:32][CH2:31][CH:30]([CH3:34])[CH3:29])[CH2:12][C@H:11]2[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)=[CH:6][CH:5]=1
Reactant: CN(C)c1ccc([C@@H]2CCNC[C@H]2COc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)CCN1CC[C@@H](c2ccc(N(C)C)cc2)[C@H](COc2ccc(C(F)(F)F)cc2)C1

Procedure:
Prepared from (41) (0.5 g), 3-methyl-1-bromobutane (0.4 g) and K2CO3 (0.5 g). Reflux for 8 h. Purification on silica gel. Yield of (69) 51%. M.p. 223.9°-225.1° C.