Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1([CH3:18])[O:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[O:7]1)[CH3:2].[H][H]>[Ni]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1([CH3:18])[O:10][C:9]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:8]=2[O:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Reactant: [H][H]
Agent: [Ni]
Product: CCOC(=O)CC1(C)Oc2ccc(N)cc2O1

Procedure:
of ethyl(2-methyl-5-nitro-1,3-benzodioxol-2-yl)-acetate (prepared according to G. Sloof, Rec. Trav. Chim. 547, 995 (1935)) dissolved in 300 cc. of 95% alcohol are hydrogenated at room temperature and 2 atm. of hydrogen pressure in the presence of 6 g. of Raney nickel. After the theoretical absorption of hydrogen, the mixture is filtered and evaporated to dryness. The residual oil is purified by distillation, (b.p. 190°-200°C./0.4 mm.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]#[C:10][C:11]([O:13]C)=[O:12])=[O:8])=[CH:5][CH:4]=1.[OH-].[K+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]#[C:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:15][CH:16]=1
Reactant: COC(=O)C#CC(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CC(=O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 6.2 g (28 mmol) of methyl 3-(4-methoxybenzoyl)propiolate in 60 ml of tetrahydrofuran was treated slowly at 0° with 80 ml of 3% potassium hydroxide solution and stirred at 0° for a further 1 hour. The reaction mixture was treated with water and extracted once with ether. The ether phase was discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Precipitation of the residue from methylene chloride/ether/hexane yielded 3-(4-methoxybenzoyl)propiolic acid as an amorphous powder.
Reaction SMILES: C(C1[CH:29]=[CH:28][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([O:24]C)=[C:19]([Cl:26])[CH:18]=2)[C:9]3=[O:27])=[CH:5][CH:4]=1)#N.Br.C[CH2:32][O:33][C:34]([CH3:36])=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[C:19]([Cl:26])[CH:18]=2)[C:9]3=[O:27])=[CH:28][CH:29]=1)=[O:35]
Reactant: CCOC(C)=O
Reactant: COc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(C#N)cc3)C2=O)cc1Cl
Agent: Br
Product: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)c(O)c(Cl)c2)C3=O)cc1

Procedure:
A mixture of the compound from Example 139 (20 mg) and aqueous HBr (5 mL) was heated under reflux for 40 minutes. EtOAc was added and the organic layer was separated. The aqueous layer was extracted with EtOAC. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc). The obtained material was dissolved in MeOH (2 mL) and few drops of SOCl2 were added. The reaction mixture was heated under reflux for 1 hour. The residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified via preparative TLC. MS m/z 449 (MH+). mp. 105.3° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH:22]CC5C=CC(OC)=CC=5)=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[N:4][CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[S:21][C:20]([NH2:22])=[N:19][N:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cncc(Cl)n4)c3c2)s1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (400 mg, 0.663 mmol) in TFA (1.5 mL). The mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 15 min, then cooled to RT. The solvent was removed in vacuo and the residue was diluted with p-dioxane (2 mL) and aq. NaOH (5 M, 0.8 mL) and the mixture was heated in a microwave at 100° C. for 15 min. The mixture was cooled to RT, diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 329 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCN(CCC)CCOCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(CCC)CCOCCN
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
The compound (128 mg) obtained in Example 90-2 was dissolved in anhydrous methanol (2.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (2.00 ml) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (81.0 mg) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:7][C:6]=2[CH:27]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccn4)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccn3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of the compound from example 1 (100 mg, 0.26 mmol) in dichloromethane (3 mL) was added triethylamine (54.4 μL, 0.39 mmol) at room temperature. The solution was cooled to 0° C. and methanesulfonyl chloride (24 μl, 0.31 mmol) was added. The reaction was stirred for a further 45 minutes. The reaction mixture was then diluted with water (5 mL) and stirred vigorously for 5 minutes. The phases were separated and the organic phase concentrated in vacuo to give the crude residue which was azeotroped with ethyl acetate to afford the product as a crystalline solid, 78 mg (65%).
Reaction SMILES: O1CCCC1.[CH3:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:9].[Br:24]Br.C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH:7]([Br:24])[CH3:6])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To 100 mL of a tetrahydrofuran solution of 24.00 g (100 mmol) of 4-benzyloxypropiophenone, a hexane solution (20 mL) of 23.973 g (1.5 equivalents) of bromine was gradually added at 20° C., followed by 1 hour of stirring. To the resulting solution, 50 mL of a saturated sodium hydrogen carbonate solution and 100 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a 20 wt % sodium thiosulfate aqueous solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. A colorless, oily substance was obtained as a result. To this substance, 200 mL of hexane was added to precipitate crystals. White crystals (31.12 g; isolation yield: 95%) of 1-[4-(benzyloxy)phenyl]-2-bromo-1-propanone were obtained as a result.
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6](Cl)=[C:5](Cl)[C:3](=[O:4])[C:2]=1Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>C(#N)C.CN(C)C=O>[C:13]1(=[O:23])[N:17]([C:1]2[C:7](=[O:8])[C:6]([N:17]3[C:13](=[O:23])[C:14]4=[CH:22][CH:21]=[CH:20][CH:19]=[C:15]4[C:16]3=[O:18])=[C:5]([N:17]3[C:13](=[O:23])[C:14]4=[CH:22][CH:21]=[CH:20][CH:19]=[C:15]4[C:16]3=[O:18])[C:3](=[O:4])[C:2]=2[N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C1C(N2C(=O)c3ccccc3C2=O)=C(N2C(=O)c3ccccc3C2=O)C(=O)C(N2C(=O)c3ccccc3C2=O)=C1N1C(=O)c2ccccc2C1=O

Procedure:
A suspension of chloranil (10.00 g, 0.04 mole) and potassium phthalimide (30.00 g, 0.16 mole) in acetonitrile is refluxed overnight. The deep purple solution is allowed to cool and then filtered, yielding a tan solid. This solid is then boiled in approximately 200 ml of dimethylformamide for ten minutes. The hot DMF suspension is then filtered yielding a white thixotropic solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH:32]1[CH2:36][CH2:35][N:34]=[C:33]1[C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][CH:38]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:45][CH2:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([C:33]4[NH:34][CH2:35][CH2:36][N:32]=4)=[CH:38][CH:39]=3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCCc1ccc(C2=NCCN2)cc1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 620.5 (MH+).
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)CSc1ccc(CC(=O)O)cc1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(CC(=O)O)cc1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [4-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:13])[C:9](=O)[O:10]C.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:27][C@H:26]([NH2:28])[CH2:25]1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C@H:24]1[CH2:25][C@H:26]([N:28]2[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]([CH3:13])[C:9]2=[O:10])[CH2:27]1
Reactant: COC(=O)N(C)c1ccccc1Br
Reactant: N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ccccc21

Procedure:
Following the procedure described for Example 44 (MethOD B6), using methyl (2-bromophenyl)(methyl)carbamate, INTERMEDIATE 74 (0.510 g, 2.089 mmol), trans-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine, INTERMEDIATE 11 (0.400 g, 1.824 mmol), tris(dibenzylideneacetone)dipalladium (o) (0.042 g, 0.046 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′biphenyl (0.049 g, 0.091 mmol), and sodium tert-butoxide (0.351 g, 3.65 mmol) in dry dioxane (5 mL) afforded the title compound 1-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (0.0811 g, 0.231 mmol, 12.69% yield) m/z: 351.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 2.55-2.65 (m, 2 H) 3.38-3.47 (m, 5 H) 4.47-4.55 (m, 1 H) 5.22 (quin, J=8.51 Hz, 1 H) 6.97-7.01 (m, 1 H) 7.06-7.16 (m, 4 H) 7.27-7.33 (m, 1 H) 7.57 (d, J=8.02 Hz, 1 H) 7.60 (dd, J=7.92, 0.68 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[I:28]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[C:6]([I:28])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(I)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 32.4 %

Procedure:
A solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one (0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) in dichloroethane, containing dichloroacetic acid (0.1 mL) was heated to reflux for 6 h under argon atmosphere. After the removal of the solvents under reduced pressure, the residue was partitioned between, dichloromethane (20 mL) and 5% sod. sulphite (10 mL). The organic phase was washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (25% EtOAc in hexane) to afford the title compound (0.125 g, 32%) as a pale yellow powder: 1H NMR (CDCl3/400 MHz) δ 7.68 (m, 1H), 7.46 (m, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 6.85 (m, 1H), 5.23 (s, 2H), and 2.38 (s, 3H); 19F NMR (CDCl3) δ−109.15 (m), −112.95 (m), −118.50 (m); ES-HRMS m/z 567.9014 (M+H C19H12NO2F4BrI requires 567.9027).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[N:30][CH:31]=3)=[CH:13][C:12]=2[F:42])[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[C:26]3[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[N:30][CH:31]=3)=[CH:13][C:12]=2[F:42])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.10 mL, 0.31 mmol) was added to a THF solution (3 mL) of ethyl 3-(5-(2-(((3′,4′-dichloro-2-fluoro-[1,1′-biphenyl]-4-yl)amino)methyl)-5-fluorophenyl)picolinamido)propanoate (60 mg, 0.10 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.Cl[C:16]1[O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>C1COCC1>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 500 ml THF cooled to -78° C. is added butyl lithium (2 eq.) followed by 4-bromobenzyl alcohol (27.2 g; 145 mmol) slowly over 45 minutes in a solution of THF (100 ml) keeping the temperature below -72° C. After 10 minutes following the final addition of the alcohol is added 2-chlorobenzoxazole (23.3 g; 145 mmol) in 25 ml THF slowly over 45 minutes. The temperature is maintained at -78° C. for 1 hour and then warmed to -40° C. for 15 minutes. The reaction is then quenched with 15 ml of acetic acid and allowed to warm to room temperature, diluted with 800 ml ether, washed 3x with H2O and brine, dried (MgSO4) and concentrated in vacuo to obtain a brown oily solid which is washed with 400 ml petroleum ether and filtered to obtain 4-(benzoxazol-2-yl)benzyl alcohol as a tan solid which is used directly in Step B.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([Br:21])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Br:21][C:12]1[CH:13]=[C:14]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)[O:8][C:9]2=[N:10][CH:11]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C
Yield: 56 %

Procedure:
A sealable tube was charged with (5S)-7-iodo-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (350 mg, 0.764 mmol), pyridin-3-ylboronic acid (94 mg, 0.764 mmol), tetrakis(triphenylphosphine)palladium (20.04 mg, 0.076 mmol) and THF (7641 μL, 0.764 mmol). The mixture was purged with Ar for 2 minutes then a solution of potassium carbonate (1.5 M) (1019 μL, 1.528 mmol) was added and the reaction vessel was sealed and heated at 110° C. for 6 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (5S)-3-bromo-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (175 mg, 0.428 mmol, 56.0% yield) as a brown foam. MS m/z=409.0 [M+H]+. Calc'd for C19H14BrN4O2: 409.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1cc(C(=O)O)ccc1N1CCCS1(=O)=O

Procedure:
Using methyl 4-amino-3-methoxybenzoate (1.22 g) and 3-chloropropane-1-sulfonyl chloride (1.1 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.05 g) was obtained.
Reaction SMILES: CC(C)([O:4][C:5](=[O:35])[CH2:6][O:7][CH2:8][CH:9]([NH:17][C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>FC(F)(F)C(O)=O>[C:5]([CH2:6][O:7][CH2:8][CH:9]([NH:17][C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([OH:35])=[O:4]
Reactant: CC(C)(C)OC(=O)COCC(Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCC(Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
(2S)-Phenylmethyl 2-[[[1-[[2-(1,1-dimethylethoxy)-2-oxoethoxy]methyl]-2-phenylethyl]amino]carbonyl]-1-pyrrolidinecarboxylate (side chain in 2 position is (±) mixture), 0.5 g (0.0010 mol), is dissolved in 30 ml of trifluoroacetic acid at 0° C. The mixture is allowed to stand 30 minutes at 0° C. and then allowed to reach room temperature over one hour and the solvent evaporated in vacuo at 25° C. The residue is dissolved in 100 ml of dichloromethane and washed with a saturated aqueous solution of sodium chloride, 2×100 ml. The dichloromethane layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue purified by chromatography using silica gel and eluting with dichloromethane methanol (95:5) to give (2S)-phenylmethyl 2-[[[1-[(carboxymethoxy)methyl]-2-phenylethyl]amino]carbonyl]-1-pyrrolidinecarboxylate (center on chain in 2 position is a mixture of isomers), 0.39 g; [α]D25 -52.2° (c 0.23, methanol).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: OB(O)c1cncnc1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncnc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with pyrimidine-5-boronic acid via General Procedure E to give, after purification by reverse HPLC, 30 mg of 6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholino-2-(pyrimidin-5-yl)furo[3,2-d]pyrimidine. MS (Q1) 460 (M+).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[O:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=O)[CH2:16][CH2:15]1>O1CCCC1>[O:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[CH:3][C:1]#[N:2])[CH2:16][CH2:15]1
Reactant: O=C1CCOc2ccccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCOc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diethyl cyanomethylphosphonate (1.15 eq.) is slowly added to a suspension of sodium hydride (1.15 eq.) in anhydrous tetrahydrofuran at 0° C. The reaction medium is stirred for 10 minutes at 0° C. and then cooled to −78° C. 4-Chromanone dissolved in tetrahydrofuran is added. The temperature is then returned slowly to 20-25° C. over 2 hours 30. After removal of the solvent, the compounds are extracted with ethyl acetate. The organic phase is washed with a large amount of a saturated solution of sodium chloride, concentrated and purified (Z/E mixture) on a silica column (AcOEt/PE 3/7).