Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH3:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]O>C(Cl)Cl>[I:25][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH3:27]
Reactant: COCc1ccccc1CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1ccccc1CI
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of imidazole (338 mg, 4.98 mmol) and triphenylphosphine (1.3 g, 4.98 mmol) in methylene chloride (10 mL) is added iodine (1.26 g, 4.98 mmol) in portions. The mixture is stirred at RT for 45 min then a solution of (2-methoxymethylphenyl)-methanol (630 mg, 4.14 mmol) in methylene chloride (3 mL) is added dropwise and stirring is continued for 3 h. The mixture is concentrated and the insoluble material is filtered. The filtrate is evaporated and the residue is purified by column chromatography using a gradient of 0-50% EtOAc/hexane as eluent to give the title compound.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:18])[CH2:9][NH:10][C:11]([CH3:17])([CH3:16])[CH2:12][NH:13][CH:14]=O)#[N:2].C([BH3-])#N.[Na+]>CO>[CH3:17][C:11]([NH:10][CH2:9][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[C:1]#[N:2])=[O:18])([CH3:16])[CH2:12][NH:13][CH3:14]
Reactant: CC(C)(CNC=O)NCC(=O)N1CCC[C@H]1C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CNCC(C)(C)NCC(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
The (S)-N-{2-[2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methyl-1-propyl}formamide (690 mg) obtained above was dissolved in MeOH (30 ml). Sodium cyanoborohydride (172 mg) was added there to and stirred for 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane:methanol 5:1→3:1) to give the title compound (455 mg, Y.:70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21]C=O)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.Cl.C(OCC)C>CO>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=CNc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc2ncnc(N3CCc4ccc(Cl)cc43)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-6-yl]-formamide (1.0055 g, 3.10 mmol) was slurried into 20 mL methanol, treated with 20 mL 1N HCl in methanol, and stirred at room temperature for one hour. Dilution to 125 mL with diethyl ether afforded yellow solid, 0.8430 g (82%; another 0.089 g obtained from subsequent cooling of mother liquor): M.P. 289°-290° C. (dec); LC-MS: 297 (MH+), 299 ((M+2)H+).
Reaction SMILES: CO.[O:3]1[CH2:5][C@H:4]1[CH2:6][N:7]([CH2:17][C@@H:18]1[CH2:20][O:19]1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC1C=CC=CC=1>[CH2:21]([N:28]1[CH2:5][C@H:4]([OH:3])[CH2:6][N:7]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:17][C@@H:18]([OH:19])[CH2:20]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccccc1)N(C[C@@H]1CO1)C[C@@H]1CO1
Reactant: NCc1ccccc1
Solvent: Clc1ccccc1
Solvent: CO
Product: O=S(=O)(c1ccccc1)N1C[C@@H](O)CN(Cc2ccccc2)C[C@H](O)C1
Temperature: 65 °C

Procedure:
Methanol (2494 kg, 18 rel. vol.—either fresh or recycled) was charged to a reaction vessel and heated to reflux temperature (approx. 65° C.). Simultaneously, and over approximately 6 hours were charged the chlorobenzene solution (containing chirally enriched N,N-bis(2(R)-oxiranylmethyl)benzenesulfonamide) from step (i), Alternative 2 above and benzylamine (109 kg, 0.91 eq.). The batch was maintained at reflux throughout the addition. The reaction was stirred at approximately 65° C. (reflux temperature) for a further 3 hours. Methanol (1938 kg, 14 rel. vol.) was then removed by distillation at atmospheric pressure before chlorobenzene (775 kg, 4 rel. vol.) was added. The resulting solution was used without further treatment in the next step (see step (iii), Alternative 2 below).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH3:65]>ClCCl.CO>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([O:64][CH3:65])=[C:58]([CH2:57][CH2:56][OH:55])[CH:63]=1
Reactant: COc1ccccc1CCO
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(Br)cc1CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
35.72 g of tetrabutylammonium tribromide are added in portions to a solution of 10.7 g of 2-(2-hydroxyethyl)-anisole in 195 ml of dichloromethane and 130 ml of methanol. The reaction mixture is stirred for 150 minutes at room temperature and is then concentrated by evaporation in a rotary evaporator. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane), yielding the title compound: Rf (dichloromethane)=0.26; HPLC Rt =13.04 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br>>[Cl:16][C:14]1[CH:15]=[CH:8][C:9]([CH2:10][N:4]2[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]2)=[CH:12][CH:13]=1
Reactant: Nc1cc[nH]n1
Reactant: Clc1ccc(CBr)c(Cl)c1
Product: Nc1ccn(Cc2ccc(Cl)cc2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 2,4-dichlorobenzyl bromide. The title compound was obtained as a light yellow solid (Yield=29%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]2[C:13]([C:17]3[CH2:18][N:19]([CH3:23])[CH2:20][CH2:21][CH:22]=3)=[N:14][NH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: C(#Cc1c[nH]nc1-c1cccnc1)CCCc1ccccc1
Product: CN1CCC=C(c2n[nH]cc2C#CCCCc2ccccc2)C1
Yield: 95 %

Procedure:
Compound 44D was converted to compound 45D, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 95% (amorphous). LCMS (method A); Rt: 1.99 min, ([M+H]+=306). 1H-NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 731-7.18 (m, 5H), 6.79-6.73 (bs, 1H), 3.43-3.40 (m, 2H), 2.78 (t, J=7 Hz, 2H), 2.60 (bt, J=7 Hz, 2H), 2.45-2.37 (m, 7H), 1.95-1.87 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=2[N:12]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2oc(S)nc2c1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (1.37 g) was dissolved in anhydrous toluene (18 ml), the resulting solution was mixed with 2-mercapto-5-nitrobenzoxazole (900 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 3 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (6.09 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain 2-(4-methyl-1-piperazinyl)-5-nitrobenzoxazole (56.1 mg) in the form of yellow crystalline powder.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[CH3:22][CH:23]([CH3:27])[CH2:24][CH2:25]Br>CN(C)C=O.O>[O:3]=[C:4]1[N:10]([CH2:25][CH2:24][CH:23]([CH3:27])[CH3:22])[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5]1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Sodium hydride 80% dispersion in oil (0.057 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.40 g) in dry dimethylformamide (15 ml). The reaction mixture was cooled to 0° and stirred for 30 min, then a solution of 3-methyl-1-bromobutane (0.23 ml) in dry dimethylformamide (4 ml) was added and stirring continued for 2 h. The reaction mixture was then diluted with water (100 ml), extracted with ethyl acetate (3×100 ml), washed with brine (2×50 ml), dried and concentrated in vacuo to give an oil which was purified by flash -chromatography (eluting with CH-EA 60:40) to give the title compound as a white solid (0.44 g). T.l.c. CH-EA (1:1), Rf=0.36.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[C:8]([CH3:14])[CH:7]=1.CN(C)C=O>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[C:8]([CH3:14])[CH:7]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Add thionyl chloride (14.31 mL, 0.2 mol) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0° C. After 1 hour at room temperature, pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to provide the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used in the next step without further purification. 1H NMR (CDCl3): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2].[NH3:21].[Cl-].[NH4+]>C(O)C>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH2:21])=[O:13])=[CH:10][C:9]=2[OH:18])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccc(C(=O)OC)cc2O)cc1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCc1ccc(Cc2ccc(C(N)=O)cc2O)cc1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a mixture of methyl 4-(4-ethylbenzyl)-3-hydroxy-benzoate (0.20 g) and 28% aqueous ammonia solution (6 mL) in ethanol (3 mL) was added ammonium chloride (0.079 g), and the mixture was stirred in sealed tube at 100° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. A mixed solvent of dichloromethane and methanol (10:1) was added to the residue, and an insoluble material was collected by filtration and dried to give 4-(4-ethylbenzyl)-3-hydroxybenzamide (0.065 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(OCC)(=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[S:7]3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: O=C1Nc2ccccc2SC1CCCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2SC1CCCCN1CCN(c2ccc(F)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 10 ml of ethyl acetate were dissolved 435 mg of 2-(4-chlorobutyl)-2H-1,4-benzothiazin-3(4H)-one and 613 mg of 1-(4-fluorophenyl)piperazine. The solvent was evaporated off, and the residue was stirred at 110° C. for one hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried (MgSO4). After removal of the solvent, the residue was subjected to a column chromatography on silica-gel (40 g). From the eluate with hexane-ethyl acetate (1:1, v/v) was obtained 2-[4-[4-(4-fluorophenyl)-1-piperazinyl]butyl]-2H-1,4-benzothiazin-3(4H)-one. The yield was 293 mg (43.2%). Recrystallization from methanol gave prisms, m.p. 150°-151° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[SH:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: Cc1ccnc(S)n1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(Sc2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Yield: 87.8 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), 2-mercapto-4-methylpyrimidine hydrochloride (1.05 g), potassium carbonate (2.76 g) and N,N-dimethylformamide (20 mL) was stirred at 110° C. under a nitrogen atmosphere for 10 hrs. The reaction mixture was diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-[4-(4-chlorophenyl)-2-[(4-methylpyrimidin-2-yl)sulfanyl]-5-oxazolepropionic acid (1.65 g, yield 88%) as colorless prism crystals. melting point: 174–175° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].C[O-].[Na+].CO>>[CH2:1]([C:8]1[C:9]([O:39][CH3:38])=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccccc1
Temperature: 53 °C
Reaction time: 5 h

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.10 g, 2.02 mmol, Example 109) and 0.5 M NaOMe in MeOH (13 mL, 6.5 mmol) in a sealed tube was heated at 53° C. for 1 hour. More 0.5 M NaOMe in MeOH (6.5 mL, 3.3 mmol) was added, and the mixture was stirred at the same temperature for another 5 hours. The solvent was evaporated in vacuo, and the residue was diluted with DMF and filtered through a syringe filter. The filtrate was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound. 1H NMR (400 MHz, CD3OD) δ 9.03 (s, 1H), 8.83 (d, J=2.02 Hz, 1H), 8.22 (d, J=2.02 Hz, 1H), 8.08 (dd, J=2.02, 8.08 Hz, 1H), 7.92 (d, J=8.59 Hz, 1H), 7.88 (d, J=8.08 Hz, 1H), 7.66 (dd, J=2.27, 8.84 Hz, 1H), 7.22 (d, J=4.04 Hz, 4H), 7.10-7.18 (m, 1H), 7.06 (d, J=1.52 Hz, 1H), 4.28 (s, 2H), 4.07 (s, 3H), 3.71 (s, 3H); MS m/e 539.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[NH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:4][CH:5]=1
Reactant: NCCCN
Reactant: C=Cc1ccncc1
Solvent: O
Product: NCCCNCCc1ccncc1

Procedure:
A mixture of 4-vinylpyridine (10.8 cm3), 1,3-diaminopropane (25 cm3) and "Triton B" (Trade Mark) (5 g; 40% solution in water) was stirred and heated at 130° for 20 hours. Water (100 cm3) was added and the mixture was extracted with chloroform (3×100 cm3). The dried (MgSO4) extracts were evaporated in vacuo to give an oil which was distilled to give 5.4 g of N-[2-(4-pyridyl)ethyl]-1,3-diaminopropane as an oil, b.p. 150°/0.03 mm. (Kugelrohr).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30](O)=[O:31])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:34]([NH2:36])[CH3:35]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:21]=[C:20]([C:30]([NH:36][O:34][CH3:35])=[O:31])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCOCC4)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCOCC2)n1

Procedure:
The title compound was synthesised by an analogous method to Example 8 starting from 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-morpholin-4-ylpyrimidine-4-carboxylic acid (Example 310) and methoxylamine hydrochloride.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[F:15])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.FC(F)(F)S(O[Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])(=O)=O>O1CCCC1>[F:3][C:4]1[C:9]([C:10]2[N:11]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:12]=[CH:13][C:14]=2[F:15])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Fc1cc[nH]c1-c1cccnc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(F)c1-c1cccnc1F
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (3.32 g) in tetrahydrofuran (70 mL) was added dropwise a solution of 2-fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridine (5.98 g) in tetrahydrofuran (30 mL) under ice-cooling and the mixture was stirred for 30 min. 15-Crown-5 (18.3 g) and tris(1-methylethyl)silyl trifluoromethanesulfonate (25.4 g) were added, and the mixture was stirred for 1 hr. The solvent was evaporated to a half volume under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.C[Si]([N:28]=[N+:29]=[N-:30])(C)C>ClCCl>[CH2:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:3]2[N:2]([CH3:1])[N:30]=[N:29][N:28]=2)[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1nnnc1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1-benzyl-piperidine-4-carboxylic acid methylamide (36) (853 mg, 3.67 mmol) in dichloromethane (10 ml) was cooled in an ice-bath and phosphorous pentachloride (841 mg, 4 mmol) was added dropwise. The mixture was stirred at rt for 5 h, cooled to −5° C. and trimethylsilyl azide (387 ul, 3.67 mmol) was added dropwise. The reaction mixture was stirred for 3 h at rt and was then quenched by addition of sat. aqueous NaHCO3 solution. The organic layer was washed with water and brine, dried over Na2 SO4 and evaporated to yield a colorless solid.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([NH:15][S:16]([C:19]1[CH:24]=[C:23]([NH:25][CH:1]=[O:2])[CH:22]=[CH:21][C:20]=1[C:26]([O:28][CH3:29])=[O:27])(=[O:18])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC=O)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6.5 ml of formic acid are carefully added at 0° C. to 13 ml of acetic anhydride. The mixture is subsequently heated at 50°-60° C. for 2 h. A solution of 16.0 g (0.056 mol) of N-tert-butyl-5-amino-2-methoxycarbonylbenzenesulfonamide in 50 ml of DMF is then added dropwise at 0° C. The cooling bath is removed and the mixture is stirred for a further 4 h at room temperature. The reaction mixture is then shaken up in 800 ml of ethyl acetate and washed with three times 150 ml of water. The organic phase is dried over magnesium sulfate, the solvent is distilled off, and the residue is recrystallized from ethyl acetate/n-heptane. The product is N-tert-butyl-5-formylamino-2-methoxycarbonylbenzenesulfonamide (14.23 g, 82% of theory) which melts at 113°-114° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][N:19]=[C:18]2[O:14][C:12]1[C:11]([F:15])=[CH:10][C:9]([F:16])=[C:8]([CH:13]=1)[NH2:7]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cc(N)c(F)cc3F)c2cc1OC
Temperature: 80 °C

Procedure:
To a stirred suspension of cesium carbonate (3.25 g, 10.0 mmoles) in dry DMF (20 mL) was added 5-amino-2,4-difluorophenol (1.00 g, 6.9 mmoles). This solution was heated to 80° C. for 1 hour, and 4-chloro-6,7-dimethoxyquinazoline (1.59 g, 7.1 mmoles) was added and the reaction heated for an additional hour. At the end of this time the reaction was poured into water (200 mL) and extracted with two portions (200 mL) of ethyl acetate. The extracts were combined and dried over MgSO4. Filtration and concentration afforded 5-(6,7-dimethoxyquinazolin-4-yloxy)-2,4-difluoroaniline as a crude red oil. Purification by silica gel chromatography eluting with an ethyl acetate/hexane gradient, 30%-70% over 70 minutes gave a slightly impure oil containing DMF. This oil was crystallized using ethyl acetate hexane to give a white solid.