Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=NC=CC=1.C[N:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)C.[ClH:17].[CH3:18][C:19]1[N:23]2[CH2:24][CH2:25][CH2:26][N:27]=[C:22]2[S:21][C:20]=1[C:28]([Cl:30])=[O:29]>N1C=CC=CC=1>[ClH:30].[ClH:17].[CH3:18][C:19]1[N:23]2[CH2:24][CH2:25][CH2:26][N:27]=[C:22]2[S:21][C:20]=1[C:28]([NH:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:29]
Reactant: CN(C)c1ccccn1
Reactant: CC1=C(C(=O)Cl)SC2=NCCCN21
Agent: Cl
Agent: Nc1cccnc1
Solvent: c1ccncc1
Product: CC1=C(C(=O)Nc2ccccn2)SC2=NCCCN21
Temperature: 25 °C
Reaction time: 20 h
Yield: 211.1 %

Procedure:
In 20 ml of pyridine was dissolved 200 mg of 3-aminopyridine. To this solution were added 50 mg of dimethylaminopyridine and 600 mg of 3-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride obtained in Example 28, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated and to the mixture was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extact was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the solution was added saturated hydrogenchloride diethylether solution. The formed crystals were collected by filtration. This crystals were recrystallized from a mixed solvent of ethanol and diethylether to obtain 300 mg of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[CH:12]=[C:11]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:10]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]3[CH3:21])[CH:12]=[C:11]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[N:10]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:34]([NH:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:35]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1N
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(CS(C)(=O)=O)cc(N3CCOC[C@@H]3C)n2)ccc1NC(=O)Nc1ccccc1
Temperature: 75 °C
Yield: 24.9 %

Procedure:
2-Methyl-4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]aniline (130 mg, 0.34 mmol) was dissolved in 1,4-dioxane (4 mL). Phenylisocyanate (0.038 mL, 0.34 mmol) was added and the reaction heated at 75° C. for 3 hours. The reaction mixture was evaporated to dryness and the resultant residue triturated with ethyl acetate to give the desired compound as a cream solid (42 mg).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino )-4-hydroxybenzoic acid, 0.05 g of 5% palaldium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : % C, 70.6; % H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].[CH:24]1([NH:27][CH2:28][C@@H:29]2[C@H:33]([F:34])[CH2:32][NH:31][CH2:30]2)[CH2:26][CH2:25]1>>[CH:24]1([NH:27][CH2:28][C@@H:29]2[C@H:33]([F:34])[CH2:32][N:31]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:23])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]4[C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:3][C:2]=3[F:1])[CH2:30]2)[CH2:26][CH2:25]1
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)c21
Yield: 37.6 %

Procedure:
Using ethyl 6,7,8-trifluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylate (50.0 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (29.0 mg), the same procedure was followed as in Example 40 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(1,1-dimethylethyl)-4-oxo-3-quinolinecarboxylic acid as a pale yellow powder (25.1 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[O:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([NH2:61])[CH2:52]1.C(N(CC)CC)C>ClCCCl>[O:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([NH:61][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])[CH2:52]1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: NC1COc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4COc5ccccc5C4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (0.0308 g, 0.0871 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.01838 g, 0.0958 mmol), 1-hydroxybenzotriazole monohydrate (0.0146 g, 0.095 mmol), and 1,2-dichloroethane (1 ml) was stirred at ambient temperature for 20 minutes. A mixture of chroman-3-amine hydrochloride (0.01780 g, 0.09589 mmol), triethylamine (0.06075 ml, 0.435 mmol), and 1,2-dichloroethane (1 ml) was added to the activated acid and the mixture was stirred for 17 hours at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 27.6 mg of the title compound as a foamy film (65%)
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1OS(C(F)(F)F)(=O)=O.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([NH:20][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: Cc1ccccc1OS(=O)(=O)C(F)(F)F
Product: CCCCNc1ccccc1C
Yield: 67 %

Procedure:
General procedure B using 55.1 mg (0.229 mmol) of o-tolyltriflate and 34.0 μl (0.344 mmol) of n-butylamine gave 67% yield of N-butyl-2-methylaniline after silica gel chromatograph using 5% ethyl acetate in hexanes.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O1CCCC1.C(O)C>[Br:13][C:9]1[N:8]=[C:7]([CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Add n-butyl lithium (16.2 mL, 2.5 M in hexanes, 40.5 mmol) dropwise to a solution of 2,6-dibromopyridine (8.00 g, 33.8 mmol) in tetrahydrofuran (100 mL) at −78° C. Stir 30 minutes then add dimethylformamide (12.3 g, 169 mmol) via syringe. Allow solution to warm to ambient temperature then pour it into a solution of sodium borohydride (17.85 g, 338 mmol) in ethanol (50 mL) at −10° C. After 10 minutes, remove the cooling bath. After 1 hour at ambient temperature, add water and 1N hydrochloric acid (gas evolution), then add saturated sodium bicarbonate solution until the mixture is neutralized. Extract the aqueous phase with ethyl acetate, dry over sodium sulfate, filter and concentrate under reduced pressure. Dissolve the residue in diethyl ether and add an excess of hydrogen chloride (2N in diethyl ether). Decant the organic phase and add saturated sodium bicarbonate solution to the residue. Extract with ethyl acetate (3×), dry over sodium sulfate, filter and concentrate under reduced pressure to afford the title compound as a brown oil (2.73 g, 14.5 mmol): MS (m/z): 189 (M+1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@@H:6]([CH3:21])[N:5]([CH:22]3[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]3)[C:4]=2[N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([NH2:40])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2.FC(F)(F)C(O)=O>C(O)C(F)(F)F.C(OCC)(=O)C>[F:29][C:25]1([F:28])[CH2:24][CH2:23][CH:22]([N:5]2[C:4]3[N:3]=[C:2]([NH:40][C:33]4[CH:34]=[C:35]5[C:39](=[C:31]([F:30])[CH:32]=4)[NH:38][N:37]=[CH:36]5)[N:11]=[CH:10][C:9]=3[N:8]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[C:7](=[O:20])[C@H:6]2[CH3:21])[CH2:27][CH2:26]1
Reactant: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Cl)nc2N1C1CCC(F)(F)CC1
Reactant: Nc1cc(F)c2[nH]ncc2c1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@H]1C(=O)N(c2cccc(C#N)c2)c2cnc(Nc3cc(F)c4[nH]ncc4c3)nc2N1C1CCC(F)(F)CC1
Temperature: 125 °C
Yield: 40 %

Procedure:
To a solution of 3-[(7R)-2-chloro-8-(4,4-difluorocyclohexyl)-7-methyl-6-oxo-7,8-dihydropteridin-5(6H)-yl]benzonitrile (208 mg, 0.5 mmol), 7-fluoro-1H-indazol-5-amine (113 mg, 0.75 mmol) in trifluoroethanol (2 mL) in a microwave reaction vial was added trifluoroacetic acid (171 mg). The vial was then sealed and heated in a microwave reactor at 125° C. for 30 minutes. The reaction mixture was then diluted with ethyl acetate (25 mL) and washed with aqueous saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4) and evaporated to give a crude material, which was then purified by silica gel column chromatography (eluent: 2% methanol in dichloromethane) to give the desired product (40%).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][C:15](ON1C(=O)CCC1=O)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([O:14][C:15]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCCBr
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Br
Solvent: ClCCl
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 0 °C
Yield: 92.1 %

Procedure:
TEA (6.91 g, 68.5 mmol) was added drop wise to an ice-cooled mixture of 3-bromopropylamine.hydrobromide (10.0 g, 45.6 mmol) and N-(Benzyloxycarbonyloxy)-succinimide (11.22 g, 47.9 mmol) in DCM (200 mL). The stirred mixture was allowed to warm to Rt overnight, then washed with water, brine, dried (MgSO4), filtered and concentrated, providing 11.43 g (92%) of N-(Benzyloxycarbonyl)-3-bromopropylamine, as a pale yellow oil. 1H NMR (CDCl3): 7.35 (m, 5H), 5.10 (s, 2H), 4.89 (br s, 1H), 3.44 (t, J=6.6 Hz), 3.35 (dd, J=12.9, 6.3 Hz, 2H), m (2.06, 2H). LCMS (LC: Hydrophobic/TFA, RT=6.4 min; MS: 294, 296 ([M+NH4]+, 22%), 272, 274 ([M+H]+, 100%).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[F:8][C:9]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>>[F:8][C:9]1[CH:27]=[C:26]([CH:28]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2F)c(C(F)(F)F)c1
Reactant: O=C1CSC(=S)N1
Product: N#Cc1ccc(Oc2ccc(C=C3SC(=S)NC3=O)cc2F)c(C(F)(F)F)c1

Procedure:
4-[2-Fluoro-4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-3-trifluoromethyl-benzonitrile was prepared using rhodanine and 4-(2-Fluoro-4-formyl-phenoxy)-3-trifluoromethyl-benzonitrile according the General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 8.41 (d, 1H), 8.11 (dd, 1H), 7.76 (d, 1H), 7.67 (s, 1H), 7.51 (m, 2H), 7.23 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](O)=[O:31])[C:25]=3[F:33])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:55][CH2:56][C:57]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH2:62][CH2:61][N:60]([CH2:63][CH2:64][OH:65])[CH2:59][CH2:58]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.O>[F:33][C:25]1[C:26]([C:30](=[O:31])[NH:55][CH2:56][C:57]2([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)[CH2:58][CH2:59][N:60]([CH2:63][CH2:64][OH:65])[CH2:61][CH2:62]2)=[N:27][CH:28]=[CH:29][C:24]=1[S:23][C:20]1[S:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:12][CH:13]=2)=[N:22][CH:21]=1
Reactant: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Reactant: NCC1(c2ccccc2)CCN(CCO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(CCO)CC4)c3F)s2)nc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
4-(2-(5-((Tert-butoxycarbonyl(methyl)amino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (0.120 g, 0.244 mmol) was diluted in NMP (4 mL) and treated with HOBT (0.043 g, 0.317 mmol), EDAC (0.094 g, 0.488 mmol) and 2-(4-(aminomethyl)-4-phenylpiperidin-1-yl)ethanol (0.074 g, 0.317 mmol) and diisopropylethylamine (0.213 mL, 1.22 mmol) at 23° C. The reaction was stirred overnight then water was added and this was extracted with ethyl acetate/THF (3×). The organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a residue which was purified on preparative HPLC (acetonitrile/water/TFA). The title material was obtained (0.140 g, ˜81%) as a solid which was used as such for the next step. LC/MS (M+H)+: 708. Ret. time: 1.612 min. (Condition F).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.C([Li])CCC.[CH3:15][C:16]1[C:24]([CH3:25])=[C:23]([CH3:26])[C:22](C)=[CH:21][C:17]=1[C:18](Cl)=O>O1CCCC1>[CH3:26][C:23]1[C:24]([CH3:25])=[C:16]([CH3:15])[C:17]([CH3:18])=[CH:21][C:22]=1[C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1cc(C(=O)Cl)c(C)c(C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(C)c(C)c(C)c1C
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A 5 L, 3-necked flask is equipped with an overhead stirrer, addition funnel, thermowell and argon inlet. The flask is purged with argon then charged with ethyl hydrogen malonate (139.8 g, 1.06 mol) and tetrahydrofuran (2.3 L). The flask is cooled to -65° C. in a dry-ice/acetone bath. The n-butyllithium (892 mL, 2.23 mol) is transferred to the addition funnel then added dropwise to the stirred solution over a 2 hour period. After complete addition the reaction is warmed to -5° C. and stirred for 15 minutes. The resulting thick slurry is cooled to -65° C. The addition funnel is rinsed with tetrahydrofuran (20 mL) and the 2,3,4,5-tetramethylbenzoyl chloride (152.6 g, 0.776 mol) in tetrahydrofuran (250 mL) is transferred to the addition funnel under argon then added dropwise to the reaction over a 1.5 hour period. After complete addition the mixture is stirred at -65° C. for 1.5 hours. The reaction is allowed to warm to -20° C. then quenched over a water-ice mixture (3 L total volume). The solution is acidified to pH 2 by the slow addition of concentrated HCl. The product is extracted with ether (3×1 L), washed with saturated NaCO3 (2×1.5 L) and brine (1×1.5 L), dried over MgSO4, then concentrated in vacuo to a tan oil. An additional reaction is carried to produce a total of 185.1 g of crude product. Attempts to purify this material by vacuum distillation result in the apparent partial decomposition of the product. The remaining material is divided into two portions with each being chromatographed over 2 kg of silica eluted with methylene chloride. The TLC pure fractions are combined, concentrated in vacuo at 40° C. to constant weight, 108.5 g (42% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14](Cl)[C:15]([Br:19])([Br:18])[CH2:16][Cl:17])[C:11](=[O:21])[N:10]([CH3:22])[C:9]1=[O:23].[Br:24][C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27].C(N(CC)CC)C.Cl>C(#N)C.C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[N:13][CH:14]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[Br:24])[C:15]([Br:19])([Br:18])[CH2:16][Cl:17])[C:11](=[O:21])[N:10]([CH3:22])[C:9]1=[O:23]
Reactant: CN1C(=O)C(=NC(Cl)C(Br)(Br)CCl)N(c2ccccc2F)C1=O
Reactant: Nc1ccccc1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CN1C(=O)C(=NC(Nc2ccccc2Br)C(Br)(Br)CCl)N(c2ccccc2F)C1=O
Reaction time: 0.17 h

Procedure:
In this example 0.02 mol of 1-(2-fluorophenyl)-3-methyl-5-(1,3-dichloro-2,2-dibromopropyl)imino-1,3-diazolidine-2,4-dione is dissolved in 20 ml of acetonitrile and then 0.02 of mol of 2-bromoaniline is added. After about 10 minutes, triethylamine is added to neutralize the byproduct HCl produced by the reaction. The mixture is stirred for five hours and 20 ml of ethyl ether is then added. The mixture is filtered and the filtrate evaporated under high vacuum affording 1-(2-fluorophenyl)-3-methyl-5-(1-2'-bromophenylamino-2,2,-dibromo-3-chloropropyl)imino-1,3-diazolidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>O1CCOCC1>[NH:12]([C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1)[NH2:13]
Reactant: NN
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(C(=O)O)ccn1
Temperature: 100 °C
Yield: 4.2 %

Procedure:
To a solution of 2-chloropyridine-4-carboxylic acid (1.57 g, 100 mmol) in 1,4-dioxane (30 mL) was added hydrazine hydrate (1.0 g, 200 mmol) dropwise at rt. The reaction mixture was heated at 100° C. overnight. The mixture was concentrated, and the residue was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to afford the title compound (650 mg, 42%) as a white solid. [M+H] Calc'd for C6H7N3O2, 154; Found, 154.
Reaction SMILES: [Li][CH2:2]CCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:41])=[CH:19][CH:18]=1.CN(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1>[Br:16][C:17]1[CH:43]=[CH:42][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH:35]([CH3:2])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:41])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CCCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Reactant: [Li]CCCC
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
n-BuLi (1.6M in hexane, 6.4 mL, 10.3 mmol) was added slowly to 2,2,6,6-tetramethylpiperidine at -10° C. and the slurry was stirred 30 min, then cooled to -78° C. and diluted with 25 mL degassed THF. This solution was transferred via cannula into a 50 mL (degassed) THF solution of ester from Step 1 (4.15 g, 9.3 mmol) at -78° C. After stirring 1-- h, HMPA (1.6 mL, 9.3 mmol) was added and 30 min later CH3I (5.8 mL, 93 mmol) was added. The reaction mixture was stirred 12 h at -78° C., then quenched with saturated NH4Cl and extracted with Et2O and ethyl acetate. The organic phase was washed with aqueous Na2S2O5, water, brine and dried over MgSO4. Purification by flash chromatography (15% ethyl acetate in hexane) provided 2.5 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>CN(C=O)C>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 150 °C

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.2 g, 0.74 mmol), (prepared as described for the starting material in Example 2), and 4-bromo-2-fluoroaniline (155 mg, 0.82 mmol) in DMF (2.5 ml) was heated at 150° C. for 45 minutes. After cooling to ambient temperature the mixture was treated as described in Example 3 to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (150 mg, 44%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.CC(O)=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[OH:1][CH2:2][CH:3]1[N:8]([CH:18]2[CH2:19][O:16][CH2:17]2)[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)C(CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
(+/−) Tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (3.07 g, 14.19 mmol), oxetan-3-one (1.820 mL, 28.4 mmol), AcOH (1.625 mL, 28.4 mmol), and 4 Å molecular sieves were taken up in DCM (16 mL) and MeOH (16.00 mL), and the reaction was stirred at room temperature overnight. Sodium cyanoborohydride (4.46 g, 71.0 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction mixture was filtered through celite, rinsing with MeOH. The solvent was removed in vacuo and the material was quenched with 2M K3PO4 solution, and then extracted 2× with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-8% MeOH/DCM). (+/−) Tert-butyl 3-(hydroxymethyl)-4-(oxetan-3-yl)piperazine-1-carboxylate (2.40 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].Br[C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:11]1[C:10]2[CH:9]=[CH:8][C:5]([CH:6]([C:14]3[CH:23]=[CH:22][C:17]([O:18][CH3:19])=[C:16]([O:21][CH3:20])[CH:15]=3)[OH:7])=[CH:4][C:3]=2[O:2][CH2:1][CH2:12]1
Reactant: Brc1ccc2c(c1)OCCO2
Reactant: COc1ccc(C=O)cc1OC
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc3c(c2)OCCO3)cc1OC
Yield: 89.4 %

Procedure:
3,4-dimethoxybenzaldehyde (2.21 g, 13.32 mmol), 6-Bromo-2,3-dihydrobenzo[1,4]dioxine (3.15 g, 14.65 mmol), and n-butyl lithium (5.86 ml, 14.65 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3,4-dimethoxy-phenyl)-methanol as an oil (3.60 g, 89%): 1HNMR (CDCl3) 6.93-6.80 (m, 6H, Ar), 5.70 (d, J=3 Hz, 1H, CHOH), 4.24 (s, 4H, CH2CH2), 3.86 (s, 6H, 2OCH3), 2.14 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.