Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH3:38])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:39]I.[H-].[Na+].[Cl-].[NH4+]>C1COCC1.ClCCl>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH3:38])[O:13][CH3:39])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CI
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.3 %

Procedure:
To a pre-cooled (0° C.) solution of the compound from Example 62, Step D (618 mg, 1.0 mmol) in THF (8 mL) was added methyl iodide (709 mg, 5.0 mmol) and NaH (60% in mineral oil) (44 mg, 1.1 mmol). The resulting mixture was stirred overnight at rt and then poured into a stirred mixture of saturated aqueous ammonium chloride (50 mL) and dichloromethane (50 mL). The organic layer was washed with water (50 mL), dried (MgSO4) and evaporated in vacuo. The resulting crude product was purified on silica gel using ethyl acetate/hexane as the eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (735 mg) as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:47]
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Product: COC1CCN(c2c(NC(=O)c3nc(-c4cc(F)ccc4F)sc3N)cnn2C)CCC1N
Yield: 33.6 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 326 (64.2 mg, 33.6% over two steps). 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1H), 8.22-8.10 (m, 1H), 7.46 (d, J=9.7 Hz, 2H), 7.45-7.35 (m, 2H), 7.34-7.18 (m, 1H), 3.64 (s, 3H), 3.23 (d, J=12.0 Hz, 4H), 3.21-2.89 (m, 6H), 2.10-1.97 (m, 1H), 1.89-1.79 (m, 1H), 1.78-1.53 (m, 2H). LCMS (ES+) m/z 478 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1/[N:9]=[N:10]/[CH2:11][CH2:12][C:13]#[N:14]>[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]1
Reactant: N#CCC/N=N/c1cc(F)ccc1F
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccnn1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
A mixture of (E)-3-((2,5-difluorophenyl)diazenyl)propanenitrile (710 mg) and 20 mL of 1N NaOH was heated to reflux with stirring for 30 min. The reaction mixture was cooled to ambient temperature and extracted with ether. The ether phase was washed with water, brine, dried over sodium sulfate and filtered through a plug of silica gel. Concentration under vacuum gave 630 mg (88%) of 1-(2,5-difluorophenyl)-1H-pyrazol-5-amine. LCMS (ESI) m+H=196.0; 1H NMR (400 MHz, CDCl3) δ 7.54-7.43 (m, 1H), 7.35-7.00 (m, 3H), 5.63 (d, 1H), 3.96-3.71 (m, 2H).
Reaction SMILES: [CH:1]([C:9]([OH:11])=O)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C)C=O.S(Cl)([Cl:19])=O>>[CH:1]([C:9]([Cl:19])=[O:11])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccccc1
Temperature: 25 °C

Procedure:
The styrene carboxylic acid copolymer (20.0g) from Example 7(b) was refluxed with stirring for 2 hours in thionyl chloride (300 ml.) containing N,N-dimethylformamide (3.0 ml.). After cooling to room temperature the mixture was filtered and the polymer washed with chloroform (5 × 100 ml., containing 2% v /v ethanol); and dried in vacuo at 40° to constant weight. The title polymer (21.80g) exhibited μ max (Nujol) 1770 and 1738 cm-1 (C=O) and was yellow-green in colour.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C[Si]([N-:52][Si](C)(C)C)(C)C.[Li+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.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].O>[C:17]1([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][O:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:52])=[N:3][CH:4]=3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(COCc2ccc(-c3ccccc3)cc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-[(4-phenylphenyl)methoxymethyl]pyridine (0.206 g) in tetrahydrofuran (10 mL), tris(dibenzylideneacetone)dipalladium (63 mg), 2-(dicyclohexylphosphino)biphenyl (48 mg), and a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 1.0 mL) were added at room temperature, and the mixture was heated to reflux for 22 hours under a nitrogen atmosphere. Hydrochloric acid (2 M, 10 mL) was added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction solution was cooled to room temperature, and sodium carbonate was gradually added thereto, and subsequently, water was added thereto, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column (Yamazen Corporation, elution solvent: dichloromethane/methanol) to obtain the title compound (0.189 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of piperidine (25 ml) and 3-(bromomethyl)benzoic acid, methyl ester (20 g) in toluene (600 ml) was stirred at room temperature for 4 h. The white preciptiate was removed by filtration and the filtrate was distilled to give the title compound as a colourless oil (17.56 g) b.p. 110° (10-1 mm). TLC silica; ether; Rf 0.7.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: CCCOc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Yield: 99.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.35 g, 2.2 mmol), 3-hydroxy-2-propoxybenzaldehyde (0.40 g, 2.2 mmol) and cesium carbonate (0.72 g, 2.2 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-2-propoxyphenoxy)-benzonitrile (0.69 g, 98%) as a brown oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:13])[C:11](=[O:12])[N:5]2C(C)(C)[O:7][CH2:8][C@@H:4]2[CH2:3]1.Cl>CO.O1CCOCC1>[F:1][C:2]1([F:13])[CH2:3][C@@H:4]([CH2:8][OH:7])[NH:5][C:11]1=[O:12]
Reactant: CC1(C)OC[C@@H]2CC(F)(F)C(=O)N21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1N[C@H](CO)CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 749.9 %

Procedure:
To a solution of (S)-6,6-difluoro-3,3-dimethyl-dihydropyrrolo[1,2-c]oxazol-5(1H,3H,6H)-one (1.35 g, 0.706 mmol) in methanol (10 mL) was added HCl in dioxane (2.65 mL, 4N) under ice-water bath and then stirred at RT overnight. The reaction mixture was concentrated. The resulting residue was dissolved in THF (10 mL) and TEA (5 mL) was added. The resulting solution was stirred for 1 h. The reaction mixture was concentrated to give a crude mixture. Purification by flash column chromatography (hexanes/EtOAc) gave (S)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one (0.80 g 75%). LRMS (M+H+)m/z 152.2.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:31][OH:32]>C(O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:31][OH:32])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a stirring suspension consisting of 1-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-phenyl-ethanone (compound A, 955 g) in ethanol (8 L) is added pyridine (4 L) and hydroxylamine hydrochloride (610 g). The resulting mixture is heated at 100° C. for two hours and subsequently stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to afford a residue that is dissolved in ethyl acetate. The solution is washed with 5% aqueous citric acid and brine. The organic layer is separated, is dried over anhydrous Na2SO4, and is concentrated under reduced pressure. The concentrate is triturated with pentane. The triturated solids are collected by filtration to afford the solid product (480 g.) The filtrate is concentrated under reduced pressure and that concentrate is triturated with pentane. The solids are collected by filtration to provide another crop of solid product (320 g), which afforded a total of 800 g of Compound B.
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9]N(CC)CC)=[CH:7][C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])=[CH:5][C:4]=1[N:23]1[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]2=[N:24]1.[OH:32][C:33]1[CH:46]=[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH:44]=[CH:43][C:34]=1[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C[O-].[Na+]>CO>[N:24]1[N:23]([C:4]2[CH:5]=[C:6]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[CH:7]=[C:8]([CH2:9][C:46]3[C:45]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:44][CH:43]=[C:34]([C:35](=[O:36])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]=3[OH:32])[C:3]=2[OH:2])[N:27]=[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=12
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reaction time: 24 h
Yield: 62 %

Procedure:
Methanol (50 ml) is placed into a 300 ml three-necked flask equipped with a stirrer, thermometer, condenser, Dean-Stark trap and nitrogen inlet. Sodium (0.3 g, 0.013 mol) is added to the methanol and the mixture stirred at room temperature till all the sodium is dissolved. Then, 2-(2-hydroxy-3-diethylaminomethyl-5-tert-octylphenyl)-2H-benzotriazole (10.2 g, 0.025 mol), 2-hydroxy-4-n-octyloxybenzophenone (8.2 g, 0.025 mol) and another 50 ml of methanol are added to the sodium methoxide solution. The reactants are heated at reflux till half the methanol is collected in the Dean-Stark trap. o-Xylene (50 ml) is added and the temperature is raised to the reflux temperature of o-xylene (143°-145° C.) and heating is continued for 24 hours. The mixture is then cooled and acetic acid is added to neutralize the sodium methoxide catalyst. The o-xylene solvent is then removed by vacuum distillation. The crude product obtained is recrystallized from heptane to afford the title compound in a yield of 10 g (62 % yield) as a white crystalline solid melting at 96°-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].Cl[C:15]1[CH:16]=[C:17]([N:26]([CH:36]([CH3:38])[CH3:37])CC2C=CC(OC)=CC=2)[C:18]2[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CC(N(C)C)=O.[Cu]I.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].CO>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:15]2[CH:16]=[C:17]([NH:26][CH:36]([CH3:38])[CH3:37])[C:18]3[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[N:20]=2)[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)#[N:6]
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C(C)C)cc1
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1cc(Nc2cc(C#N)cc(C(F)(F)F)c2)nn2c(C#N)cnc12
Temperature: 125 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.078 g, 0.42 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 10A (0.100 g, 0.281 mmol), cesium carbonate (0.366 g, 1.124 mmol), copper(I) iodide (0.027 g, 0.141 mmol), Xantphos (0.033 g, 0.056 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. The solids were removed via filtration through CELITE® and washed with THF. The dark brown filtrate was concentrated under reduced pressure and then diluted with water and ethyl acetate. The layers were separated, and the aqueous phase extracted with ethyl acetate (2×10 mL). The organics were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL), and treated with triethylsilane (0.45 mL, 2.8 mmol), and TFA (0.3 mL) at room temperature. After 20 min., the volatiles were removed via a stream of nitrogen. The residue was triturated with MeOH, forming a white precipitate. The solid was isolated via filtration, washed with MeOH, and suspended in 1:1 1N HCl/MeCN and lyophilized, affording Example 10, (0.081 g, 68.3% yield) as a white solid. HPLC: Rt=4.35 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=386.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.24 (1H, s), 8.19 (1H, s), 7.82 (1H, s), 7.48 (1H, d, J=8.03 Hz), 5.94 (1H, s), 2.52-2.55 (1H, m), 1.28 (6H, d, J=6.27 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([OH:16])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:15][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC(O)C1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC1CC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 94.2 %

Procedure:
N-(Benzyloxycarbonyl)-3-amino-1-cyclobutanol (2.22 g, 10 mmol) from Step B and t-butyldimethylsilyl chloride (4.8 g, 32 mmol) were combined in 25 mL of anhydrous pyridine and the cloudy suspension was stirred over the weekend at ambient temperature, under a nitrogen atmosphere. After 65 h, the solution was concentrated in vacuo at 35°-40° C. The concentrate was diluted with 250 mL of methylene chloride and the methylene chloride solution was washed with 3×100 mL of water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue (3.9 g) was purified on a 1.0×45 cm silica gel column eluted @ 5 psi with 100 mL of hexane, followed by 200 mL of 10% acetone in hexane to give 3.16 g (88% yield) of the title compound; MS DCI-NH3M/Z: 336 (M+H)+, 353 (M+NH4)+ ; 1H NMR (CDCl3) δ - 0.03 (s, 6H), 0.83 (s, 9H), 1.75 (m, 2H), 2.68 (m, 2H), 3.69 (m, 1H), 3.93 (m, 1H), 5.06 (s, 2H), 7.30 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:30][CH:31]=[CH:32][C:33]=1B(O)O)(=[O:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:23]([O:26][CH2:27][C:28]1[C:29]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:30][CH:31]=[CH:32][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20]([CH3:22])[CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(OC4CN(C)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 39.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 5-bromo-1-methyl-3-(5-(1-methylazetidin-3-yloxy)pyridin-2-ylamino)-pyridin-2(1H)-one 206f (108 mg, 0.40 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diaza-tricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), Pd(dppf)Cl2 (20 mg, 0.02 mmol), K3PO4 (180 mg, 0.80 mmol), sodium acetate trihydrate (120 mg, 0.80 mmol), water (0.5 mL), and acetonitrile (10 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 207a (100 mg, 45%) as a yellow brown solid. LCMS-ESI: [M+H]+ 638.4.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[C:8](SC)[NH:7][CH:6]2[CH3:17].[OH-].[NH4+:20].[OH-].[Na+].OO>C(#N)C.O>[Cl:2][C:3]1[C:4]([CH3:18])=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[C:8]([NH2:20])[NH:7][CH:6]2[CH3:17]
Reactant: [NH4+]
Reactant: COc1cc(Cl)c(C)c2c1N=C(SC)NC2C
Agent: I
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cc(Cl)c(C)c2c1N=C(N)NC2C
Temperature: 170 °C

Procedure:
6-Chloro-8-methoxy-4,5-dimethyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (119 mg, 0.30 mmol) was suspended in a mixture of ammonium hydroxide (0.22 ml, 25% in H2O, 3 mmol) and acetonitrile (0.9 ml), and heated in a microwave oven to 170° C. (30 min). The reaction was cooled in an ice bath and treated with 1N aqueous sodium hydroxide solution (0.9 ml) and 5-6 drops of concentrated solution of aqueous hydrogen peroxide. A little water was added, and the crude product precipitated and was filtered off. It was purified by column chromatography (silica gel, ethyl acetate/acetone/acetic acid=12/4/1) and was set neutral with 1N aqueous sodium hydroxide solution to yield after drying the title compound as a light grey solid (45 mg, 63%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:61]=[C:60]2[C:56]([CH:57]=[C:58]([C:62](O)=[O:63])[NH:59]2)=[CH:55][CH:54]=1)=[O:51])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:58]2[NH:59][C:60]3[C:56]([CH:57]=2)=[CH:55][CH:54]=[C:53]([NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])[CH:61]=3)=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)O)[nH]c2c1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
HATU (0.104 g, 0.272 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.056 g, 0.182 mmol), 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.050 g, 0.182 mmol) and DIPEA (0.048 mL, 0.272 mmol) in DMF (1.5 mL). The mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.056 g, 48%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 9.74 (s, 1H), 7.78 (s, 1H), 7.44 (d, 1H), 7.27-7.37 (m, 2H), 7.21 (dd, 1H), 7.08-7.13 (m, 1H), 6.98 (d, 1H), 6.74-6.86 (m, 3H), 6.63 (s, 1H), 4.66 (d, 2H), 1.50 (s, 9H). MS: m/z 569 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:13]([C:14](=[O:16])[CH3:15])[C:8]=2[O:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:13]([CH:14]([OH:16])[CH3:15])[C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2c(C(C)=O)c(OCc3ccc(Cl)cc3Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1coc2c(C(C)O)c(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
To a mixture of methyl(7-acetyl-6-((2,4-dichlorobenzyl)oxy)-1-benzofuran-3-yl)acetate (100 mg) in MeOH (2.5 mL) was added NaBH4 (10.2 mg). The mixture was stirred at room temperature for 20 min. The mixture was quenched with water. The resulting solid was collected by filtration to give the title compound (89 mg).