Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:45]1([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH2:58])=[CH:53][CH:52]=2)[CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([N:12]([CH2:14][C:15]2[O:19][CH:18]=[C:17]([C:20]([NH:58][CH2:57][C:54]3[CH:53]=[CH:52][C:51]([CH2:50][N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[CH:56][CH:55]=3)=[O:22])[CH:16]=2)[CH3:13])(=[O:11])=[O:10])=[C:4]([Cl:23])[CH:3]=1
Reactant: NCc1ccc(CN2CCCC2)cc1
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(=O)NCc2ccc(CN3CCCC3)cc2)co1)S(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 5-({[(4-bromo-2,6-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (40 mg, 0.09 mmol), EDCI (23 mg, 0.12 mmol) and HOBt (15 mg, 0.11 mmol) in DMF (3 mL) was added 1-[4-(pyrrolidin-1-ylmethyl)phenyl]methanamine (17 mg, 0.09 mmol). The reaction was stirred at ambient temperature for 3 days, then absorbed on to an Isolute SCX-2 cartridge, washing with MeOH and eluting the product with 7M NH3 in MeOH. The filtrate was concentrated in vacuo and a portion of the crude product purified using prep method C.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:33])=[C:24]([CH:32]=1)[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26]>CS(C)=O>[C:1]12([CH2:11][O:12][C:21]3[C:20]([Cl:19])=[CH:32][C:24]([C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[O:26])=[C:23]([F:33])[CH:22]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
To a mixture of adamantan-1-ylmethanol (1.00 g, 6.0 mmol) in anhydrous dimethyl sulfoxide (40 mL) was added potassium t-butoxide (1.68 g, 15.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min followed by the addition of 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (1.62 g, 6.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (200 mL). The organic layer was washed with water (2×40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 0.2% acetic acid) in hexanes as an eluent to afford the title compound as a white solid (1.17 g, 46%): 1H NMR (300 MHz, DMSO-d6) δ 12.10 (s, 1H), 7.77 (d, J=7.5 Hz 1H), 7.23 (d, J=12.5 Hz, 1H), 3.72 (s, 2H), 3.35 (s, 3H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H); 13C NMR (75 MHz, DMSO-d6) δ 162.3 (d, J=2.2 Hz), 159.8 (d, JC-F=255 Hz), 158.3 (d, JC-F=11 Hz), 130.6 (d, JC-F=4 Hz), 116.8 (d, JC-F=3 Hz), 113.6 (d, JC-F=14 Hz), 102.7 (d, JC-F=28 Hz), 79.1, 41.2, 38.5, 36.4, 33.4, 27.3; MS (ES−) m/z 414.1, 416.1 (M−1).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@@H:24]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:25]([O:27]C)=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:6]=1.Cl.[Li+].[Cl-]>CO.O.O1CCOCC1>[NH2:4][C:5]1[N:10]=[C:9]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][N:17]([C:21]([NH:23][C@@H:24]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:25]([OH:27])=[O:26])=[O:22])[CH2:18]3)=[CH:13][CH:12]=2)[CH:8]=[C:7]([N:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)[N:6]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCc2ccc(-c3cc(N4CCN(C)CC4)nc(N)n3)cc2C1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (7.1 mg, 0.17 mmol) was added to a mixture of methyl (2S)-2-({[7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}amino)-3-phenylpropanoate (30 mg, 0.057 mmol) in methanol (0.6 mL) and water (0.2 mL). The reaction mixture was stirred at r.t. overnight, and adjusted with 4N HCl in 1,4-dioxane to pH=5. The volatiles were removed under reduced pressure to afford the product which contaminated with LiCl and was directly used for next step reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C@@H:9]([CH3:22])[C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:18]([O:17][C:15](=[O:16])[NH:14][C@H:10]1[C@H:9]([CH3:22])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:11]1=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H](Nc1ccccc1N)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2S,3S)-3-(2-amino-phenylamino)-2-tert-butoxycarbonylamino-butyric acid (5.29 g, 17.1 mmol) in N,N-dimethylformamide (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.26 g, 22.2 mmol) and the reaction was stirred at ambient temperature for 24 h. The mixture was concentrated in vacuo, diluted with water (100 ml) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to give ((2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester which was used in the subsequent step without further purification (4.55 g, 91%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])C1C=CC=CC=1.[H][H]>[Pd].CCOC(C)=O>[Si:16]([O:15][CH2:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][NH:8]1)([C:19]([CH3:22])([CH3:20])[CH3:21])([CH3:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1COCCN1
Yield: 99.9 %

Procedure:
A suspension of (R)-4-benzyl-3-((tert-butyldimethylsilyloxy)methyl)morpholine (576 mg, 1.79 mmol) and 10% palladium on carbon in EtOAc (20 mL) was placed in a Parr shaker and hydrogenated at 45 psi hydrogen pressure for 48 h. The heterogeneous mixture was filtered through a pad of diatomaceous earth, washed with CH3OH (200 mL) and concentrated to provide (R)-3-((tert-butyldimethylsilyloxy)methyl)morpholine (414 mg, quant.) as a colorless oil. MS consistent.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Cl[C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][N:33]=1>>[C:36]([C:35]1[CH:39]=[CH:40][C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:29]=2)=[N:33][CH:34]=1)(=[O:37])[NH2:38]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)cn4)ccc3o2)CC1
Yield: 16.3 %

Procedure:
Following the General Procedure-3, the titled compound (40 mg) was prepared from Intermediate 14 (250 mg, 0.6 mmol) and 6-chloronicotinamide (94 mg, 0.6 mmol) as an off-white solid. M.P.: 227-230° C. MS (m/z): 409.1 [M+H]+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[Cl:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Cc1cccc(N)c1Cl
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: Cc1cccc(Nc2c(Nc3ccccc3O)c(=O)c2=O)c1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-chloro-3-methylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 329 (M+).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH:14]=[N:15][NH:16][C:17]([NH2:19])=[NH:18])([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[C:21]([C:20]1[C:9]2[CH2:10][C:11]([CH2:14][NH:15][NH:16][C:17]([NH2:19])=[NH:18])([CH3:13])[O:12][C:8]=2[CH:7]=[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]=1[OH:4])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=NNC(=N)N)O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1(CNNC(=N)N)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Yield: 75.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 1.0 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methylideneamino]guanidine in 10 ml of tetrahydrofuran was added dropwise to a suspension of 0.98 g of lithium aluminum hydride in 20 ml of tetrahydrofuran at room temperature. After heating under reflux for 14 hours, a saturated aqueous ammonium chloride was added under ice-cooling, insoluble matters were filtered off on Celite and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 0.68 g of 1-[(4,6-di-t-butyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran-2-yl)methylamino]guanidine as a pale yellow oil (yield 76%).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C@@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8]1)(=O)C.O.NN>[Cl-].[Na+].O>[NH2:4][CH2:5][CH2:6][C@@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8]1
Reactant: COc1ccc2c(c1)[C@@H](CCNC(C)=O)CC2
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)[C@@H](CCN)CC2
Yield: 97.1 %

Procedure:
A mixture of (R)-1-[2-(acetylamino)ethyl]-6-methoxyindan (50 mg, 0.21 mmol) and hydrazine hydrate (1 ml) was heated under reflux for 26 hours under argon atmosphere. The reaction mixture was cooled, to which was added brine, followed by extraction with chloroform. The extract solution was washed with brine, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 39 mg (yield 95%) of (R)-1-(2aminoethyl)-6-methoxyindan as an oily product. This product was dissolved in chloroform (0.8 ml), to which was added triethylamine (57 μL, 0.41 mmol), and the mixture was cooled with ice. To the mixture was added dropwise trifluoroacetic anhydride (43 μL, 0.31 mmol), which was stirred for 20 minutes. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 7:3) to give 41 mg (yield 70%) of the above-titled compound, m.p.65-66° C. (recrystallized from isopropyl ether/hexane). [α]Hg365 −51.8° (c 0.3, CHCl3)
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH2:11]([C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:27](=[O:28])[CH2:26][CH2:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:20]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: c1cc2c(o1)CCNC2
Reactant: O=C(O)CCc1cccc(CCc2ccccc2)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1cccc(CCc2ccccc2)c1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.163 g (1.021 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.29 g (1.1 mmol) of 3-(3-phenethylphenyl)propionic acid and 0.57 ml (4.1 mmol) of triethylamine in 30 ml of dichloromethane, 0.23 ml (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[NH:29][C:28](=[O:42])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 90.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one 3e obtained from step 4 of Example 3 as starting materials to obtain (Z)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-o ne 55 (77 mg, yield 90.8%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][CH3:24])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:22]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[C:3]([NH:23][CH3:24])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)OC)cc1)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)O)cc1)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 421.6 %

Procedure:
To methyl 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoate (0.05 g, 0.15 mmol) was dissolved in dioxan (2 ml) and to it was added sodium hydroxide (0.012 g, 0.3 mmol) in water (0.5 ml) and the mixture stirred for 4 hr at room temperature. The solvent was removed under vacuum and the residue acidified, extracted with ethyl acetate (2×10 ml), dried over anhydrous sodium sulfate and concentrated to provide 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (0.2 g, 41%). RP-HPLC: 1.8 min; ES-MS (M+H)+=317.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][OH:14])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:6]=2[N:7]=1
Reactant: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (142 mg) in chloroform (10 ml) was added triethylamine (77 μL) and methanesulfonyl chloride (49 μL). Stir at room temperature for 2 hours then partition between chloroform and brine, the combined organics were dried (MgSO4). The solvents were removed in vacuo to yield methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](Cl)[C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][N:8]=2)[N:3]=1.Cl.Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CN(C)[C@H]1CC[C@H](Nc2c(S(C)(=O)=O)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, 2,8-dichloro-7-(methylsulfonyl)-1,5-naphthyridine (140 mg, 0.52 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (140 mg, 0.65 mmol) to afford the desired product (68 mg, 34%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 5.06-4.96 (m, 1H), 3.09 (s, 3H), 2.33 (s, 6H), 2.33-2.28 (m, 2 H), 2.27-2.17 (m, 1 H), 2.06-1.99 (m, 2H), 1.56-1.32 (m, 4H); ESI MS m/z 383 [M+H]+
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.B1C2CCCC1CCC2.Cl[C:25]1[CH:26]=[C:27]([C:40]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]([N:47]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)[N:41]=2)[C:28]([NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[N:29][CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[CH3:56][O:55][C:52]1[CH:51]=[CH:50][C:49]([CH2:48][N:47]([CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)[C:42]2[N:43]=[C:44]([CH3:46])[N:45]=[C:40]([C:27]3[CH:26]=[C:25]([CH2:1][CH:2]4[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]4)[CH:30]=[N:29][C:28]=3[NH:31][C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[N:41]=2)=[CH:54][CH:53]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 140 °C
Yield: 70.8 %

Procedure:
tert-Butyl 4-methylenepiperidine-1-carboxylate (0.117 g, 0.592 mmol) was treated with 9-BBN (0.5 M in THF, 1.183 mL, 0.592 mmol) and the mixture was heated at reflux for 4 h. After cooling, the resulting solution was transferred into a stirred mixture of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.288 g, 0.493 mmol), Pd2(dba)3 (0.023 g, 0.025 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.049 mmol), and Na2CO3 (0.131 g, 1.233 mmol) in 1,4-dioxane (1.0 mL) and water (0.25 mL). The mixture was sealed and heated under microwave at 140° C. for 30 min. After cooling, the resulting mixture was passed through a short path of Celite® (diatomaceous earth), washing with EtOAc (3×10 mL). The combined organic phases were concentrated and purified by flash chromatography (short column, SiO2, pure hexanes→30% EtOAc in hexanes) to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperidine-1-carboxylate (0.261 g, 0.349 mmol, 70.9% yield) as a sticky yellow syrup. m/z (ESI, +ve ion) 747.2 (M+H)+.
Reaction SMILES: BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.[Br:39][C:40]1[N:45]=[C:44]([C:46](=[O:49])[NH:47][CH3:48])[C:43]([NH:50][C:51]2[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[C:76]([O:77][CH3:78])=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:71]CC)[O:68][CH2:69][CH3:70])=[C:64]([Cl:79])[CH:63]=3)[N:52]=2)=[CH:42][CH:41]=1>>[Br:39][C:40]1[N:45]=[C:44]([C:46](=[O:49])[NH:47][CH3:48])[C:43]([NH:50][C:51]2[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[C:76]([O:77][CH3:78])=[CH:75][C:65]([CH2:66][P:67](=[O:71])([OH:74])[O:68][CH2:69][CH3:70])=[C:64]([Cl:79])[CH:63]=3)[N:52]=2)=[CH:42][CH:41]=1
Reactant: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl

Procedure:
Prepared analogously to Compound 38C replacing Compound 38B with diethyl (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56C). 1H NMR (400 MHz, DMSO-d6) δ=12.39 (br. s., 1H), 9.18 (br. s., 1H), 8.91-8.99 (m, 1H), 8.49 (s, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.64 (br. s., 1H), 7.16 (d, J=2.0 Hz, 1H), 3.95 (quin, J=7.3 Hz, 2H), 3.77 (s, 3H), 3.22-3.27 (m, 2H), 2.81 (d, J=5.1 Hz, 3H), 1.18 (t, J=6.9 Hz, 3H). MS (ESI): m/z 653.02/655.02 [M+H]+. UPLC: tR=0.89 min (polar—2 min).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25](=O)[N:26]([CH3:28])[CH3:27])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][N:26]([CH3:28])[CH3:27])[CH:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Agent: B
Solvent: C1CCOC1
Product: CN(C)Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)ccn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-[(2-Dimethylcarbamoyl-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (28 mg, 0.05 mmol) was added a solution of 1.0M borane-tetrahydrofuran (2 mL). The reaction was stirred at room temperature for 24 h. The reaction was quenched with 1N HCl (2 mL) and concentrated in vacuo to an oil. Reverse phase chromatography (C-18 using acetonitrile/0.1% trifluoroacetic acid in water) gave upon concentration in vacuo EXAMPLE 51.