Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11](=[O:28])[NH:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=S)[NH2:2].IC.CC(C)=O.C([O-])(=O)C.[NH4+:41]>ClCCl.CO>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([NH:10][C:11](=[O:28])[NH:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[NH:41])[NH2:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(=N)N)cc2)cc1
Yield: 7.1 %

Procedure:
In a similar manner to Example 1, t-butyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (4.4 g) was reacted with iodomethane (25 ml) and acetone (450 ml) and the resultant product was treated with ammonium acetate (10 g), methanol (400 ml) and dichloromethane (100 ml) at ambient temperature. This yielded a crude yellow solid (1.2 g), which was triturated with methanol, collected, washed with methanol and then stirred with 50% aqueous acetic acid solution (15 ml). Any solid material was filtered and discarded and the filtrate was evaporated and triturated under a mixture of ether and methanol to give the title compound (300 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 1.77 (1.8H, s), 4.62 (2H, s), 6.90 (2H, d), 7.49 (2H, d), 7.92 (2H, d), 8.15 (2H, d), 9.50-10.4 (3H, br), 10.60 (1H s); Mass Spectrum m/Z 413 (M+H)+ ; Elemental Analysis: calculated for C21H24N4O5. 0.6 CH3CO2H. 1.5 H2O: C, 56.0%; H, 6.2%; N, 11.7%; found: C, 56.3%; H, 6.2%; N, 11.1%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:10][CH:9]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=2)[CH2:10][C@H:9]1[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccccc1S(=O)(=O)OC1=CC(=O)N(C(=O)OC(C)(C)C)C(C(=O)OCc2ccccc2)C1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CC(=O)N(C(=O)OC(C)(C)C)[C@H](C(=O)OCc3ccccc3)C2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2.75 g of 6-oxo-4-(toluene sulfonyloxy)-3,6-dihydro-2H-pyridine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester in 18 ml of tetrahydrofuran are added 1.4 g of 4-methoxyphenylboronic acid, 3.15 g of potassium phosphate, 0.12 g of ′ic′cl′hexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (X-PHOS) and 22 mg of palladium acetate under argon. The reaction mixture is heated to 80° C. for 2 hours, cooled to room temperature, diluted with ethyl acetate and the organic phase is washed with water and dried over sodium sulfate. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a brown solid. Rf=0.35 (EtOAc-heptane 1:2); Rt=4.95.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1.NC1C=NC(C)=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:34]([NH:33][C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)=[O:35])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Agent: Cc1ccc(N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cc4)c3)CC2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5) and phenyl 6-methylpyridin-3-ylcarbamate (123 mg, 0.541 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-amino-6-methylpyridine) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (50-100% EtOAc:CH2Cl2) to afford the title compound (220 mg) as a white solid. MS APCI M+ 468.2, 375.2, 334.1 M− 466.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.41-2.45 (m, 2H) 2.46 (s, 3H) 2.54 (td, J=5.90, 1.26 Hz, 2H) 3.50-3.55 (m, 2H) 3.58-3.65 (m, 2H) 6.43 (s, 1H) 6.91-6.96 (m, 2H) 7.06-7.12 (m, 3H) 7.20 (d, J=8.52 Hz, 1H) 7.35-7.42 (m, 1H) 7.59-7.68 (m, 2H) 7.77 (dd, J=8.45, 2.62 Hz, 1H) 8.43 (d, J=2.78 Hz, 1H).
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1.C(O)(=O)C>CS(C)=O>[CH2:2]([O:9][C:11]1[N:12]([C:21]2[N:22]=[C:23]([NH2:29])[NH:24][C:25](=[O:28])[C:26]=2[N:27]=1)[C@@H:13]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Nc1nc2c(nc(OCc3ccccc3)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Temperature: 65 °C

Procedure:
Two hundred mL of dimethyl sulfoxide (DMSO) are added to a freshly prepared solution of sodium benzoylate (made from benzyl alcohol (75 mL) and sodium (2.14 g)) under an atmosphere of argon. 8-Bromodeoxyguanosine (10 g, 29 mmol) in DMSO (80 mL) is added to the resulting mixture and the reaction is heated to 65° C. for 24 hours. After cooling to room temperature, the reaction mixture is neutralized with glacial acetic acid and the DMSO is removed by vacuum distillation at 65° C. The remaining solution is poured into ether with stirring. The oily residue that remains after decanting off the ether is added to acetone and the resulting white precipitate is removed by filtration. After stirring with water, the slurry is filtered and the collected white solid recrystallized from methanol to give 8-(benzyloxy)-2'-deoxyguanosine.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[Br:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1>C(O)(=O)C>[Br:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1ccsc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1sccc1Br
Reaction time: 0.17 h

Procedure:
7.4 ml of fuming nitric acid was slowly added to 92.1 ml of acetic acid under ice-cooling, followed by stirring for 10 minutes, and a solution of 52.1 ml of acetic anhydride containing 25 g of 3-bromothiophene was slowly added in such a manner that the bulk temperature did not exceed 10° C., followed by stirring at 10 ° C. for 2 hours. Ice was added to the reaction solution, and the resulting crystals were collected by filtration, and washed with water and diethyl ether/n-hexane=1/5 successively, to give 17.4 g of the title compound.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)SC)#[N:2].[CH3:18][NH2:19]>>[C:1]([NH:3][C:4]([NH:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)#[N:2]
Reactant: CSC(=NCCSCc1cnccn1)NC#N
Reactant: CN
Product: CNC(=NCCSCc1cnccn1)NC#N

Procedure:
Reaction of this isothiourea with methylamine by the procedure of Example 3(c) (ii) gives the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[O:16])[C:8]([O:12][CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][N:28](CCN(C)C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCOC(C)=O.CCCCCC>CN(C=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:27]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[O:16])[C:8]([O:12][CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1)#[N:28]
Reactant: CN(C)CCN(C)C
Reactant: CCOc1nc2cc(Br)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1nc2cc(C#N)ccc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 160 °C
Yield: 265.6 %

Procedure:
To a solution of 600 mg (1.44 mmol) 7-bromo-2-ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 32) in DMF (3 mL) were added 46 μL (0.32 mmol) TMEDA, 102 mg (0.86 mmol) zinc cyanide, 2 mg (0.007 mmol) Pd2dba3 and Xantphos. The reaction solution was degasses and flushed with nitrogen three times and then heated in MW to 160° C. for 4 min. After cooling to RT the mixture was filtered through celite and it was washed with dichloromethane. The combined organic layers were concentrated in vacuo. After CC (EtOAc/hexane 1:2) of the residue, 310 mg (0.85 mmol, 59%) 7-Cyano-2-ethoxy-N-[(3-fluorophenyl)-methyl]-4-methyl-quinoline-3-carboxylic acid amide (example 36) were obtained. MS: m/z 364.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([O-:29])=[O:28])=[C:15]([S:18][C:19]4[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:30](=[O:31])[N:13]3[C:14]([C:27]([OH:29])=[O:28])=[C:15]([S:18][C:19]4[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncccc1SC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N#Cc1ncccc1SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirring solution of (7R)-7-[(phenylacetyl)amino]-3-(2-cyanopyrid-3-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester (158 mg, 0.277 mmol) and anisole (0.4 mL) in dichloromethane (1 mL) at 0° C. was added trifluoroacetic acid (1 mL). After 1 h at 0° C., the solvent was removed with a rotary evaporator, and the residue was triturated with ether, filtered, and dried, affording 104 mg (83%) of the title compound. 1H NMR (CDCl3) δ3.15 (d, 1, J=18), 3.54 (d, 1, J=18), 3.65 (d, 1, J=16), 3.69 (d, 1, J=16), 5.07 (d, 1, J=4), 5.89 (dd, 1, J=4, 9), 6.18 (d, 1, J=9), 7.2-7.4 (m, 5), 7.53 (dd, 1, J=5, 8), 7.90 (d, 1, J=8), 8.66 (d, 1, J=5).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCCC>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:33]([C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:36])([F:37])[F:26])=[CH:30][CH:31]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCCC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.445 g) and 4-(trifluormethoxy)aniline (0.3 g) was dissolved in toluene (20 ml) under an argon atmosphere at RT, dimethylaluminium chloride in heptane (0.9 molar, 3.8 ml) was added and the mixture was refluxed for 3 hours. It was then cooled to RT, water (1 ml) was added and the reaction mixture was then stirred for 10 min. The solvent was evaporated off, the residue absorbed on silica gel and purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%) to give 8-(2-chloro-benzenesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one as a white solid. MS (ESI): 489.08 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[O:8][CH2:9][C:10](=O)[NH:11][C:6]2=[CH:5][CH:4]=[CH:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[CH:7]2[O:8][CH2:9][CH2:10][NH:11][C:6]2=[CH:5][CH:4]=[CH:3]1
Reactant: CN1C=CC=C2NC(=O)COC21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C=CC=C2NCCOC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (424 mg, 2.58 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran under nitrogen atmosphere, and then cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (5.16 ml, 5.16 mmol) was added thereto dropwise and then stirred for 30 minutes. The reaction temperature was raised to room temperature and then stirred for 1 hour. The reaction mixture was cooled to 0□ again and water (0.2 ml), 10% sodium hydroxide solution (0.4 ml) and water (0.6 ml) were added thereto dropwise in this order, and stirred vigorously at room temperature for 1 hour. The formed precipitate was filtered and washed with excess ethyl acetate. The filtrate was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain 5-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (100 mg, 26% in two steps).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[CH:4].C(N(CC)CC)C.[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][CH2:2][C:3]#[CH:4])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#CCN
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a dichloromethane (25 mL) solution of amino-2-propyne (0.96 g, 17.43 mmol) and triethylamine (3.33 mL, 23.7 mmol) at 0° C. was added 3-phenoxybenzoyl chloride (3.68 g, 15.8 mmol) in dichloromethane (25 mL) in a dropwise fashion. The reaction was stirred for 1 h after removing the cooling bath and partitioned between dichloromethane and 10% aqueous HCl. The layers were separated and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed (1×, saturated sodium bicarbonate; 1×, brine), dried (MgSO4), and concentrated under vacuum to give a golden oil. Recrystallization with ehter ethyl acetate provided the title compound as a colorless solid (2.95 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].ClC1N=NC(N)=C(C)C=1.C([O-])(O)=O.[Na+].[Br:24]Br>CO.CCOC(C)=O>[Br:24][C:4]1[C:3]([CH3:9])=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: Cc1cc(N)nnc1Cl
Reactant: BrBr
Agent: Cc1cc(Cl)nnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(Cl)nnc(N)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of 6-chloro-5-methylpyridazin-3-amine and 3-chloro-5-methylpyridazin-6-amine (1.45 g, 10 mmol) from 1a and NaHCO3 (2.1 g, 25 mmol) were suspended in MeOH (20 mL) and treated with Br2 (0.57 mL, 11 mmol). The mixture was stirred at room temperature for 4 h, then filtered. The filtrate was condensed in vacuo. The resulting residue was resuspended in EtOAc (100 mL) and washed sequentially with sat. aqueous NaHCO3 solution (2×20 mL) and aqueous NaCl solution (1×20 mL). The solution was dried over MgSO4. The solvent was removed in vacuo to give crude 4-bromo-6-chloro-5-methylpyridazin-3-amine (1 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]1[O:23][CH2:22]1>>[OH:23][CH2:21][CH2:22][N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:1]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: C1CO1
Product: CCCCCCCCCCCCCCCCCCN(C)CCO
Temperature: 160 °C
Yield: 86.6 %

Procedure:
An autoclave provided with a stirrer, a thermometer, a pressure gauge and a pressure dropping funnel was charged with 250 g of N-methyloctadecylamine and heated to 160° C. Then 45 g of ethylene oxide was occasionally added dropwise thereto under a pressure of 0 to 6 kg/cm2G. Three hours were required for completing the addition. Next, the resulting mixture was aged, i.e., maintained, at 160° C. for 2 hours and then cooled. The reaction mixture was taken out and distilled to thereby give 250 g of N-(2-hydroxyethyl)-N-methyloctadecylamine. This product had a boiling point of 185 to 190° C. /0.2 mmHg.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: C1CNCCNC1
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Product: c1ccc2c(c1)OCC(COc1nccnc1N1CCCNCC1)O2

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and homopiperazine (266 mg, 2.66 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 105 mg (57%) of the title product. Anal. (C18H24N4O3) H, N; C: calcd, 63.14; found, 62.70.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:30][CH2:31][CH2:32]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:30][CH2:31][CH2:32][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: OCCCl
Reactant: Oc1cccc2[nH]ccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCOc1cccc2[nH]ccc12
Temperature: 23 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
To 2.0 g (1.5 mmol) 4-hydroxyindole in 50 mL THF at 0° C. is added 6.3 g (24 mmol) Ph3P, 1.51 mL (1.81 g, 22.53 mmol) 2-chloroethanol and 3.78 mL (4.19 g, 24.03 mmol) diethylazodicarboxylate. After stirring at 23° C. for 20 h, the dark reaction mixture is evaporated to a black oil. Diethyl ether (30 mL) is added, the dark solution stirred on a magnetic stir plate, and 200 mL hexanes is added (to precipitate Ph3PO). After stirring at 23° C. for 30 min, the mixture is filtered and the filtrate evaporated to a light yellow oil. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (8/1 to 4/1), gives 1.13 g (5.78 mmol, a 39% yield) of the title compound as an off-white solid. MS (ES) m/z 196 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[C:4]([NH:6][C:7](=[S:10])[SH-]C)=[S:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>C1(C)C=CC=CC=1>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:17]([Cl:16])[CH:18]=1)=[S:10])=[S:5]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C[SH-]C(=S)NC(=S)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: S=C(NC(=S)c1c(Cl)cccc1Cl)Nc1ccc(Cl)c(Cl)c1

Procedure:
3.0 g of N-(2,6-dichlorothiobenzoyl)-S-methyl-dithiocarbamate and 1.6 g of 3,4-dichloroaniline are dissolved in 25 ml of toluene and subsequently heated while refluxing for 5 hours. The resulting yellow precipitate is worked up in the usual manner. Yield 2.1 g. Melting point 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([NH2:15])[C:5](Br)=[C:4]([O:17][CH2:18][CH3:19])[N:3]=1>CO.CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC(O)=O.CC(O)=O.[Pd]>[NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([NH2:15])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[C:4]([O:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCOc1nc(N)c(C(=O)OC(C)(C)C)c(N)c1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOc1nc(N)c(C(=O)OC(C)(C)C)c(N)c1C(=O)OC

Procedure:
Prepared analogously to example 377e by carbonylation of the product obtained in (842c) using 1,1′-bis-diphenylphosphino-ferrocene, palladium-II-acetate and TEA in methanol and DMF.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([O:17][CH2:18][C:19]1([CH2:23][CH2:24][CH3:25])[CH2:22][O:21][CH2:20]1)(=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].C(N(CC)CC)C>ClCCl>[CH2:11]([C:10]12[O:16][CH2:20][C:19]([CH2:23][CH2:24][CH3:25])([CH2:18][O:17]1)[CH2:22][O:21]2)[CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCC(=O)OCC1(CCC)COC1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCCCC12OCC(CCC)(CO1)CO2
Temperature: 25 °C

Procedure:
Boron trifluoride etherate (0.18 ml) was added to a stirred solution of (3-propyloxetan-3-yl)methyl hex-5-ynoate (1.33 g.) in dry dichloromethane (25 ml) at -70° C. The mixture was allowed to warm to room temperature over 16 hours. Triethylamine (0.28 ml) was then added and the solvent was removed in vacuo. The residue was partitioned between diethyl ether and water. The organic phase was separated and further washed with water and brine before drying over anhydrous magnesium sulphate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on alumina eluting with 1:6 dichloromethane:hexane saturated with ammonia. 1-(Pent-4-ynyl)-4-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless oil which crystallised on trituration (0.64 g) with hexane.