Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:10]Cl)[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3].[CH3:12][O:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:4]([CH2:10][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5](=[O:9])[CH:6]([Cl:8])[Cl:7])[CH:2]=[CH2:3]
Reactant: COCCO
Reactant: C=CCN(CCl)C(=O)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN(COCCOC)C(=O)C(Cl)Cl

Procedure:
A solution of N-allyl-N-chloromethyldichloroacetamide (21.7 g., 0.1 mole) and 2-methoxyethanol (8.4 g., 8.7 ml., 0.11 mole) in dry chloroform (50 ml.) is placed in a round-bottomed, four-necked flask of 250 ml, equipped with a calcium chloride tube, reflux condenser, mechanical stirrer, dropping funnel and thermometer. Triethylamine (10.1g., 13.9 ml., 0.1 mole) is added under stirring and external cooling in such a rate that the temperature does not exceed 35° C. After the addition is complete, the mixture is stirred for an additional 2 hours at room temperature. The mixture is washed with water (2×70 ml) for removing the triethylamine hydrochloride formed, the chloroform solution is dried over anydrous sodium sulfate and, after distillation of the chloroform, the product is dried under reduced pressure to give 23.6 g. (92%) of a pale yellow oil which is the named compound of 95% purity according to an analysis by gas chromatography; nD25 =1.4801. This product is directly useful for practical purposes.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:12]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:10].CN1CCOCC1>ClCCl>[CH3:6][CH2:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C:2]([O:4][CH3:5])=[O:3])[N:12]1[C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[O:10]
Reactant: CCOC(=O)C1CCC(CNCC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCC(CN(CC(=O)OC(C)(C)C)C(=O)OC)N1C(=O)OC(C)(C)C
Yield: 88.3 %

Procedure:
Methyl chloroformate (0.065 mL, 0.85 mmol) was added to a solution of 5-[(tert-butoxycarbonylmethyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (300 mg, 0.77 mmol) and 4-methylmorpholine (0.12 mL, 1.2 mmol) in dichloromethane (10 mL) at 0° C. After 15 minutes the mixture was diluted with dichloromethane (30 mL) and washed with water (15 mL), saturated ammonium chloride (15 mL) and saturated sodium chloride (15 mL). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to provide 5-[(tert-butoxycarbonylmethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (304 mg, 0.68 mmol, 88%). C21H36N2O8 calculated 444.3, observed [M+1]+445.3; rt=2.58 min.
Reaction SMILES: [Se](=O)=[O:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:15])=[N:12]2)=[CH:7][CH:6]=1>O1CCOCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH:15]=[O:2])=[N:12]2)=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(Br)cc2n1
Solvent: C1COCCO1
Product: O=Cc1ccc2ccc(Br)cc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 124.8 %

Procedure:
Selenium dioxide (1.6 g, 14 mmol, 1.3 eq) was suspended in dioxan (50 mL) and was heated to 60° C. At this temperature 7-bromoquinaldine (2.5 g, 11.2 mmol) was introduced and the mixture was left at 80° C. for 3 hours. After cooling the mixture to room temperature, the crude slurry was filtered on celite, eluted with dioxan and concentrated under reduced pressure. The product was obtained pure as a brown solid (3.3 g, >98%) that was used without furter purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH:24]([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([F:25])[F:26])=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1ccc(OCC(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1ccc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (340 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (214 mg, 0.81 mmol) and 1-(3-chloro-4-(2,2-difluoroethoxy)phenyl)ethanamine hydrochloride (200 mg, 0.74 mmol, Amine-24, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:19][C:20]1[O:24][CH:23]=[C:22]([C:25]([OH:27])=O)[CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)([Cl:30])=O>C(Cl)Cl>[CH2:1]([O:19][C:20]1[O:24][CH:23]=[C:22]([C:25]([Cl:30])=[O:27])[CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)O)co1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOc1cc(C(=O)Cl)co1
Reaction time: 5 h

Procedure:
To a cooled mixture of 40.0 g (0.106 mole) of 5-(cis-9-octadecen-1-yloxy)-3-furoic acid in methylene chloride is added 30 ml of thionyl chloride. The mixture is stirred for 5 hours. Then the solvent and excess thionyl chloride is removed under reduced pressure affording the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride. A mixture of 11.6 g (0.100 moles) of methyl acetoacetate and 2.3 g of sodium in 1 liter of benzene is refluxed for 20 hours, then cooled, and the crude 5-(cis-9-octadecen-1-yloxy)-3-furoyl chloride is added over a two hour period. The mixture is refluxed for 6 hours, cooled by the addition of ice and mixed well. The benzene layer is separated, washed with 5% sodium bicarbonate solution and dried. The benzene is distilled off under reduced pressure yielding 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetoacetic acid, methyl ester. To a solution of 3.3 g of ammonium chloride in 15 ml of water at 40° C is added 10 g of the above ester maintaining the temperature at 40° C for 15 minutes followed by rapid cooling. The solution is extracted with ether, the extract dried, and evaporated to dryness affording 2-[5-(cis-9-octadecen-1-yloxy)-3-furoyl]acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH2:17])=[O:9])[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCC(C(=O)c2cc(F)ccc2N)CC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: CN1CCC(C(=O)c2cc(F)ccc2Nc2ccccc2[N+](=O)[O-])CC1

Procedure:
By analogous procedures as in Examples 6 and 10, using the corresponding starting materials, 2-amino-5-fluorophenyl 1-methyl-4-piperidyl ketone is prepared and reacted with o-chloronitrobenzene to give 5-fluoro-2-(o-nitroanilino)-phenyl 1-methyl-4-piperidyl ketone. This intermediate is then reduced and cyclized in the presence of an acidic catalyst to give 2-fluoro-11-(1-methyl-4-piperidyl)-5H-dibenzo-[b,e][1,4]diazepine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)[N:34]=1.[CH2:54]([C@@H:59]1[O:61][C@H:60]1[CH2:62]O)[CH2:55][CH2:56][CH2:57][CH3:58]>C(Cl)(Cl)Cl>[F:32][C:33]1[C:38]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[N:37][CH:36]=[C:35]([C:47]2[CH:48]=[CH:49][C:50]([O:53][CH2:62][C@H:60]3[C@H:59]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[O:61]3)=[CH:51][CH:52]=2)[N:34]=1
Reactant: CCCCCCCCc1ncc(-c2ccc(O)cc2)nc1F
Reactant: CCCCC[C@@H]1O[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ncc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1F
Yield: 40 %

Procedure:
In an analogous reaction to Example 5a, 3.04 g (11.60 mmol) of triphenylphosphine, 1.82 ml (11.60 mmol) of diethyl azodicarboxylate, 2.00 g (7.00 mmol) of 2-fluoro-3-octyl-6-(4-hydroxyphenyl)pyrazine and 1.67 g (11.60 mmol) of (2S,3S)-3-pentyloxiran-2-ylmethanol give 1.20 g of [(2S,3S)-3-pentyloxiran-2-yl]methyl 4-(2-fluoro-3-octylpyrazin-6-yl)phenyl ether of [α]D20 (c = 0,995 in CHCl3)=-16.58. ##STR28##
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[C:4]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC.C1COCC1>[CH3:1][O:2][CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH3:14])[CH2:4]1
Reactant: COC1C(=O)N(C)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1CN(C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 1028.5 %

Procedure:
Dissolve methoxy-3-methyl-1,3,4,5-tetrahydrobenzo[d]azepin-2-one (375 g, 183 mmol, 1.0 eq) in THF (2.5 L) and add the solution via an addition funnel over 1 hour to slurry of lithium aluminium hydride (LAH) (175 g, 457 mmol, 2.5 eq) in ether/THF (4.5 L/2 L) in a 22 L reaction vessel under nitrogen while cooled in an ice/acetone bath. Add the starting amide at a rate to maintain the reaction temperature below 30° C. Stir the resulting mixture for 3 hours at room temperature under nitrogen. The reaction is determined to be complete by TLC. Cool the reaction mixture in an ice/acetone bath and quench slowly over 2 hours (off-gassing, exothermic) with water (175 mL) and 5.0 N NaOH solution (350 mL) added in succession. Filter the slurry and wash the solids with THF. Add sodium sulfate to the filtrate to remove any excess water, and then filter. Concentrate the filtrate down under vacuum to a dark oil to obtain the product methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (360 g, quantitative yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=3)[C:10](=[O:24])[CH:9]=2)=[CH:2]1.P(Br)(Br)[Br:26]>C(Cl)Cl>[Br:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 220 mg (0.68 mmol) 4-(furan-3-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 5.1a) in 8.0 mL of DCM is added at 0° C. 44 μL (0.47 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with ice water. The layers are separated, the aqueous phase is extracted three times with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with (S)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) to give the title compound as a colourless oil, MS (ESI+): m/z=410.1 [M+H]+.
Reaction SMILES: [Cl:1]C(C1C=CC=CN=1)(Cl)Cl.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:14][C:13]=1C(Cl)(Cl)Cl.ClCl>>[Cl:1][C:13]1[CH:14]=[C:15]([C:18]([Cl:21])([Cl:20])[Cl:19])[CH:16]=[N:17][C:12]=1[Cl:11]
Reactant: ClC(Cl)(Cl)c1ccccn1
Reactant: Clc1ncc(C(Cl)(Cl)Cl)cc1C(Cl)(Cl)Cl
Agent: ClCl
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
Seventy-five grams of a mixture containing 24.3% 3,5-bis(trichloromethyl pyridine and 6.5% 6-chloro-3,5-bis(trichloromethyl)pyridine were chlorinated with 70 grams per hour of chlorine at 190° C. for 8 hours. Analysis is listed in Table 8. The 5,6-dichloro-3-trichloromethyl pyridine concentration went from zero to 0.5% and the 2,6-dichloro-3,5-bis(trichloromethyl)pyridine went from zero to 0.7%. The 3,5-bis(trichloromethyl)pyridine went from 24.3% to 18.1% while the 6-chloro-3,5-bis(trichloromethyl)pyridine increased from 6.5% to 14.0%. Temperatures below 190° C. give unacceptably slow reaction rates to produce 5,6-dichloro-3-trichloromethyl pyridine and 2,3,5,6-tetrachloropyriidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:27])[C:9](=[O:26])[CH2:10][NH:11][C:12](=[O:25])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH:22][CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:28])[C:3]=1[CH2:29][Br:51]
Reactant: BrC(Br)(Br)Br
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
To a mixture of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene (8.10 g) in dichloromethane (81 ml) was added triphenylphosphine (5.66 g) and carbon tetrabromide (8.95 g) at 0° C. After 15 minutes the reaction mixture was stirred at ambient temperature for 3 hours. To the mixture was added triphenyiphosphine (1.42 g) and carbon tetrabromide (2.39 g) and stirred for another 2 hours. The reaction mixture was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the mixture was filtered and evaporated in vacuo. The residue was purified by flash column chromatography eluting with dichloromethane:ethyl acetate (1:1, V/V) and dichloromethane:methanol (20:1, V/V) followed by crystallizing from ethyl acetate to give 2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl)amino]benzyl bromide (6.40 g) as pale yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:16][C:17]=3[C:18]32[N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)=[C:9]([F:34])[CH:8]=1)(=O)=O.BrC1C=C2[C:51]3([N:56]=[C:55](N)[CH2:54][O:53][CH2:52]3)C3C=C(Cl)N=CC=3OC2=CC=1.N1CCOCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:34][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:27]4[C:28]([F:33])=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][CH:13]=3)[C:18]3([N:25]=[C:24]([NH2:26])[CH2:23][O:22][CH2:21]3)[C:19]=2[CH:20]=[C:7]([N:56]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)[CH:8]=1
Reactant: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: NC1=NC2(COC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: NC1=NC2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Temperature: 25 °C
Yield: 550 %

Procedure:
A re-sealable vial was charged with 5-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.379 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-isopropoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) 1 (27.6 mg, 0.038 mmol) and 0.5 ml of THF. The mixture was stirred at RT until all solids were dissolved. Morpholine (66.1 μL, 0.758 mmol) and LiHMDS (1M in THF) (1138 pt, 1.138 mmol) were added and the vial was sealed and stirred at RT for 20 minutes. The reaction was quenched by addition of water (1 ml) and diluted with EtOAc (2 ml). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×2 ml). The combined organic fractions were concentrated and purified by chromatography (10-80% DCM/MeOH/NH4OH in DCM) to provide racemic 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholino-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (97 mg, 0.209 mmol, 55.1% yield).
Reaction SMILES: CS[C:3]1[C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:11]=[C:12]([N:13]3[CH2:18][CH2:17][S:16](=[O:19])[CH2:15][CH2:14]3)[C:7]=2[N:6]=[CH:5][N:4]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:3]1[C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:11]=[C:12]([N:13]3[CH2:14][CH2:15][S:16](=[O:19])[CH2:17][CH2:18]3)[C:7]=2[N:6]=[CH:5][N:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12
Reactant: NCc1ccccc1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccccc4)ncnc23)CC1

Procedure:
1.9 gm (0.005 mol) of 8-methylthio-4-(1-oxido-thiomorpholino)-2-piperazino-pyrimido-[5,4-d]-pyrimidine (m.p.: 253°-255° C.) were heated with 25 ml of benzylamine for about one hour at 150° C. Subsequently, the excess amine was largely distilled off in vacuo, the residue was taken up in about 150 ml of water, and the solution was adjusted to pH 7 with dilute hydrochloric acid. The precipitated reaction product was suction-filtered off, washed with water and dried.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:20]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]>C(N(CC)CC)C>[C:20]([C:23]1[S:27][C:26]([C:2]2[N:6]3[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][C:5]3=[N:4][CH:3]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CCOC(=O)CCCNc1ccc2ncc(Br)n2n1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1ccc2ncc(-c3ccc(C(C)=O)s3)n2n1
Yield: 74 %

Procedure:
The ethyl 4-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)butanoate was subjected to Suzuki coupling with (5-acetylthiophen-2-yl)boronic acid, using triethylamine as the base and the procedure described in example 5.6.19 to give 74% yield of the product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][CH2:13][C:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]([O:12][CH2:13][C:14]2([CH2:17][OH:18])[CH2:16][CH2:15]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OCC1(CO)CC1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)ccc1OCC1(CO)CC1
Temperature: 50 °C
Yield: 70.4 %

Procedure:
A solution of 1-fluoro-4-iodo-2-nitrobenzene (2.50 g, 9.4 mmol) in DMF (30 mL) was treated with 1-(hydroxymethyl)cyclopropylmethanol (1.91 g, 19 mmol) and K2CO3 (2.6 g, 19 mmol) and the mixture was heated at 50° C. for 8 hours. TLC indicated complete consumption of the arylfluoride. The mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. Purification by flash column chromatography (EtOAc in heptanes) gave the titled compound as a light yellow solid (2.31 g, 71% yield). 1H NMR (400 MHz, DMSO) δ 8.15 (d, J=2.2 Hz, 1H), 7.92 (dd, J=8.8, 2.2 Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 4.60 (t, J=5.6 Hz, 1H), 4.05 (s, 2H), 3.36 (d, J=5.6 Hz, 2H), 0.50 (s, 4H).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].Cl>N1C=CC=CC=1>[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 0.181 g (1.0 mmol) of 5,6-dihydrophenanthridine in 2 ml of warm pyridine is added 0.273 g (1.0 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred overnight at room temperature, 1.2 ml of 2N HCl added. The solid which separates is filtered and washed with water. The solid is dissolved in dichloromethane and the solution washed with 2M sodium carbonate. The organic layer is concentrated and the residue chromatographed twice on silica gel with ethyl acetate-hexane as solvent to give 79 mg of crystals, m.p. 190°-194° C. Mass Spec-FAB 419 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]1=[O:18].[H][H]>O1CCCC1.[Ni]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:12]2=[O:18])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCCCOC1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1cc(N)ccc1N1CCCCOC1=O

Procedure:
1.95 g (7.79 mmol) 3-(2-methyl-4-nitro-phenyl)-[1,3]oxazepan-2-one are dissolved in 200 ml of tetrahydrofuran and combined with 700 mg Raney nickel. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 1 bar hydrogen pressure for four hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:14]>CC(N(C)C)=O>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[CH2:24][CH2:25]1)[CH3:14]
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc4cc(F)ccc4n3)CC2)ccc1OC
Yield: 3.6 %

Procedure:
A solution of 2-chloro-6-fluoro-quinoline (27.2 mg, 0.15 mmol, 1.0 equiv; intermediate D1) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 220° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.2 mg (4%) of the title compound. MS (ISP): 410.4 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13]/[CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[O:1]=[C:2]1[N:10]2[C:13]([CH2:14][CH2:15][NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][N:11]=[C:9]2[N:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2
Reactant: CCCCCn1/c(=N/N=C\CCNC(=O)OCc2ccccc2)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCNC(=O)OCc3ccccc3)nnc12
Yield: 54.8 %

Procedure:
A mixture of benzyl (3Z)-3-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]propylcarbamate (4.0 g, 5.6 mmol) in acetic acid (50 mL) was refluxed in the air overnight. The mixture was concentrated and purified by preparative LCMS to give the desired product (1.3 g, 54% yield) as a white solid. LCMS calculated for C21H26N7O3 (M+H): 424.2; found: 424.2.