Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH2:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][C:22]#[CH:23].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
A solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28, 3.4 g, 10.0 mmol), benzyl but-3-ynylcarbamate (17, 2.0 g, 10 mmole), and triethylamine (20 mL) in anhydrous THF (60 mL) pre-cooled to −78° C. was degassed with argon. The mixture was warmed to room temperature and dichlorobis(triphenylphosphine)palladium(11) (PdCl2(PPh3)2 (702 mg, 1 mmole) and CuI (381 mg, 2 mmole) were added rapidly in one portion under argon. The mixture was heated at 60° C. for 4 h, then at room temperature for 48 h. The reaction mixture was filtered through a plug of diatomaceous earth and the filtrate was partitioned between EtOAc (500 mL) and 1 N HCl (200 mL). The aqueous layer was separated and back-extracted with EtOAc (300 mL). The combined organic extracts were washed with water (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silical gel, 10:1 hexanes/EtOAc) to afford carbamate 29 (1.24 g, 37%) as a brown thick oil: 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H), 5.13 (s, 2H), 3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CS(C)=O.CC(C)([O-])C.[K+].Br[CH2:28][C:29]#[N:30]>C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:28][C:29]#[N:30])=[O:8]
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene -2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)]in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HC1. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. An additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:31]=[N:30][C:16]3[NH:17][CH2:18][CH2:19][N:20]([CH2:21][C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[CH:14]=2)=[CH:9][CH:8]=1>>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[CH2:21][N:20]1[CH2:19][CH2:18][NH:17][C:16]2[N:30]=[CH:31][C:13]([C:10]3[CH:11]=[N:12][C:7]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)=[CH:14][C:15]1=2
Reactant: C1CCNC1
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(-c4ccc(Cl)nc4)cc32)c1
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(-c4ccc(N5CCCC5)nc4)cc32)c1
Temperature: 87 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
Pyrrolidine (1 mL) was added to 7-(6-chloropyridin-3-yl)-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (49 mg), and the mixture was stirred at 87° C. for 16 hours. The reaction mixture was then concentrated, and CH2Cl2 and H2O were added. The organic phase was isolated, dried with magnesium sulfate, filtered and then purified by normal phase column chromatography eluting with 3% methanol in CH2Cl2 to give the title compound as a yellow solid (36% yield). M.p.>200° C., LCMS: m/z=440.19 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.99 (4H, m), 3.47 (6H, m), 3.64 (2H, t, J=4.0 Hz), 4.47 (2H, s), 4.98 (1H, bs), 6.35 (1H, d, J=8.8 Hz), 6.52 (1H, d, J=1.8 Hz), 7.18 (1H, dd, J=8.3, 2.5 Hz), 7.26 (1H, m), 7.32 (1H, d, J=8.6 Hz), 7.48 (1H, dd, J=8.7, 2.4 Hz), 7.62 (1H, d, J=1.8 Hz), 8.17 (1H, d, J=2.3 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[NH:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[NH:4]1
Reactant: C1=COCCC1
Reactant: O=C1N[C@@H](CO)CS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N[C@@H](COC2CCCCO2)CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-3 (3.3 g, 25 mmol) and 20 mg of p-toluenesulfonic acid in CH2Cl2 (100 mL) was added 3,4-dihydro-2H-pyran (2.7 mL, 30 mmol) and the resulting solution was stirred at rt for 30 minutes. Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 40% EtOAc/hexanes to yield 4 g of 3-4 as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.0 (br s, 1H), 4.6 (s, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.6 (m, 3H), 3.3 (dd, 1H), 1.9–1.4 (m, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Octyl chloroformate (23.1 g, 0.12 mol) was added to and reacted with a solution of p-hydroxybenzaldehyde (III) (16 g, 0.18 mol) dissolved in dry pyridine (100 ml), followed by allowing the reaction mixture to stand overnight, thereafter extracting it with toluene, washing the organic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, and distilling off toluene to obtain p-octyloxycarbonyloxybenzaldehyde (IV) (33.2 g), dissolving this compound (20.5 g, 0.07 mol) in acetic acid (60 ml), dropwise adding a solution of anhydrous chromic acid (14 g, 0.14 mol) dissolved in water (11 ml) and acetic (17 ml) to the above solution being agitated, keeping the inner temperature at 40° C. on a water bath for 4 hours after completion of the dropwise addition, thereafter cooling the reaction mixture, adding water (300 ml), filtering the deposited crystals, recrystallizing from ethanol to obtain p-hexyloxycarbonyloxybenzoic acid (V) (7 g), adding thereto thionyl chloride (10 ml), heating the mxiture under reflux for one hour, and distilling off excess thionyl chloride to obtain the objective p-hexyloxycarbonyloxybenzoic acid chloride (VI) (7.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:4][CH:3]=1.C[CH2:23][CH2:24][C:25]([CH2:27][C:28]([O-])=[O:29])=O.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([C:25]1[CH2:27][C:28](=[O:29])[C:3]2[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:10](=[O:19])[C:11]4=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]4[C:13]3=[O:14])[CH:4]=2)[N:1]=1)[CH3:23]
Reactant: CCCC(=O)CC(=O)[O-]
Reactant: Nc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC1=Nc2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)C1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of N-(2-(4-aminophenoxy)ethyl)phthalimide (4.2 g), methylpropionylacetate (1.94 g) and p-toluenesulphonic acid (100 mg) in benzene (95 ml) was stirred and heated at reflux for 3 hours with azeotropic removal of water. Volatile material was then removed by evaporation and the residue was added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (25 ml). The mixture was heated at reflux for 15 minutes and then cooled to ambient temperature. Hexane (80 ml) was added to the mixture which was triturated to give a solid. The solid was collected by filtration and washed with hexane. Ethyl acetate (70 ml) was added to the solid and the mixture was heated at reflux for 5 minutes and then cooled in an ice-bath. The undissolved solid was collected by filtration and washed with ethyl acetate to give 2-ethyl-6-(2-phthalimidoethoxy)-4-quinolone (2.5 g) as an off white solid, m.p. 168°-171° C.; NMR (d6 -DMSO): 1.24(t, 3H), 2.59(q, 2H), 4.0(t, 2H), 4.28(t, 2H), 5.87(s, 1H), 7.18(dd, 1H), 7.45(m, 2H), 7.84(m, 4H), 11.4(br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:24][N:23]=[N:22][N:21]=3)[CH:15]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc(-c2nnn[nH]2)c1
Yield: 58 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 3-chloro-2-methylbenzenesulfonyl chloride (12.4 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 58% yield (10.1 mg). MS (ESI+) calcd mass for C14H12ClN5O2S 349.040023, found 349.040413.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:8][C:7](=[O:24])[N:6]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([F:33])[CH:26]=2)[N:5]=1)(=O)[NH2:2].[ClH:34].O1CCOCC1.CCOCC>C(Cl)Cl>[ClH:34].[C:31]([C:28]1[CH:29]=[CH:30][C:25]([N:6]2[C:7](=[O:24])[CH:8]=[C:9]([O:10][CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:4]([C:1]#[N:2])=[N:5]2)=[CH:26][C:27]=1[F:33])#[N:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C(N)=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1ccc(-n2nc(C#N)c(OC3CCNCC3)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirring solution of tert-butyl 4-(3-cyano-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate (example 34) (22 mg, 0.050 mmol) in DCM (3 mL) at room temperature under argon was added 4 M HCl in dioxane (0.375 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight. Et2O (10 mL) was added to the reaction mixture. The solid product was collected by filtration and further washed with ether (2 mL×2). After drying under vacuum for 2 hours, 19 mg (100%) of 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carbonitrile HCl salt was obtained as an off-white solid. MS (ESI) 340 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([N:14]4[CH2:17][CH:16]([OH:18])[CH2:15]4)[S:13][C:9]=3[CH:8]=2)[CH:4]=[N:3]1.C(N(CC)C(C)C)(C)C.[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([S:39](N2C=NC=N2)(=[O:41])=[O:40])=[CH:35][CH:34]=1)([O-:32])=[O:31].C(N(CC)CC)C>ClCCl>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([S:39]([O:18][CH:16]2[CH2:17][N:14]([C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)[CH:20]=[CH:19][C:10]=4[N:11]=3)[CH2:15]2)(=[O:41])=[O:40])=[CH:37][CH:38]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2cncn2)cc1
Reactant: Cn1cc(-c2ccc3nc(N4CC(O)C4)sc3c2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nc(N4CC(OS(=O)(=O)c5ccc([N+](=O)[O-])cc5)C4)sc3c2)cn1

Procedure:
A suspension of 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-ol (Reference Example 2, 0.143 g, 0.50 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and 1-(4-nitrophenylsulfonyl)-1H-1,2,4-triazole (0.178 g, 0.70 mmol) in dichloromethane (5.0 mL) was stirred a few hours and then triethylamine (0.14 mL, 1.0 mmoL) was added. After the mixture had been stirred overnight additional 1-(4-nitrophenylsulfonyl)-1H-1,2,4-triazole (0.076 g, 0.30 mmol) was added. The mixture was stirred another day and then placed directly onto a column of silica and purified chromatographically (100% CH2Cl2 to 80:20 CH2Cl2/ethyl acetate) to give 1-(6-(1-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)azetidin-3-yl 4-nitrobenzenesulfonate. 1H NMR (300 MHz, CD3OD) δ ppm 3.91 (s, 3H), 4.20-4.25 (m, 2H), 4.46-4.52 (m, 2H), 5.41-5.50 (m, 1H), 7.46 (d, J=8 Hz, 1H), 7.52 (dd, J=1, 8 Hz, 1H), 7.79 (s, 1H), 7.87 (s, 1H), 7.92 (s, 1H), 8.24 (d, J=9 Hz, 2H), 8.51 (d, J=9 Hz, 2H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([P:22]([CH3:25])([CH3:24])=[O:23])[N:11]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:10]=1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])C1C=CC=CC=1>CO.[Pd]>[CH3:24][P:22]([C:12]1[N:11]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:10]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])=[C:9]([OH:8])[C:13]=1[OH:14])([CH3:25])=[O:23]
Reactant: COc1ccc(-n2c(C(=O)N(C)C)c(OCc3ccccc3)c(OCc3ccccc3)c2P(C)(C)=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-n2c(C(=O)N(C)C)c(O)c(O)c2P(C)(C)=O)cc1
Yield: 68.3 %

Procedure:
A solution of 3,4-bis(benzyloxy)-5-(dimethylphosphoryl)-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (66) (29 mg, 0.054 mmol) in MeOH (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford 5-(dimethylphosphoryl)-3,4-dihydroxy-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (UL1-125) (13 mg, 67%) as a pale yellow solid: m/z 353 (M+H)+ (ES+), 351 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.35 (s, 1H), 8.55 (s, 1H), 7.23-7.14 (m, 2H), 6.96-6.88 (m, 2H), 3.77 (s, 3H), 2.86 (br s, 6H), 1.33 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:24]2([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]([F:30])=[CH:12][N:11]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:40](B3OC(C)(C)C(C)(C)O3)=[N:39][N:38]([C:50]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:35]2=[N:36][CH:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[F:30][C:13]1[C:14]([NH:16][CH:17]([C:24]2([CH3:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:15][C:10]([C:40]2[C:34]3[C:35](=[N:36][CH:37]=[C:32]([F:31])[CH:33]=3)[N:38]([C:50]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[N:39]=2)=[N:11][CH:12]=1
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)OC1(C)C
Reactant: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)CC(Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1F)C1(C)CCCC1
Temperature: 135 °C
Reaction time: 1 h

Procedure:
A solution of K3PO4 (0.464 g, 2.183 mmol), racemic ethyl 3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-(1-methylcyclopentyl)propanoate, 147a, (0.180 g, 0.546 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 135a, (303.4 mg, 0.6004 mmol) in 2-Methyl THF (3.240 mL) and H2O (0.360 mL) was degassed under a stream of nitrogen for 30 minutes. To this mixture was added X-phos (0.031 g, 0.066 mmol) and Pd2(dba)3 (0.013 g, 0.014 mmol). The reaction mixture was stirred at 135° C. in a pressure tube for 1 hour. The organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 240 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.55 (dd, J=8.5, 2.7 Hz, 1H), 8.15 (d, J=2.4 Hz, 2H), 7.27 (dd, J=11.0, 5.0 Hz, 15H), 5.38 (d, J=9.7 Hz, 1H), 4.89 (dd, J=9.7, 6.0 Hz, 1H), 3.99 (q, J=7.1 Hz, 2H), 2.73 (dd, J=14.7, 3.8 Hz, 1H), 2.52 (dd, J=14.8, 9.4 Hz, 1H), 1.68 (dd, J=12.0, 6.6 Hz, 2H), 1.64-1.52 (m, 4H), 1.47-1.36 (m, 1H), 1.30 (dt, J=14.3, 7.2 Hz, 2H), 1.11-0.99 (m, 4H). LCMS Gradient 60-98%, formic acid, 7 minutes, C18/can, Retention Time=3.24 minutes (M+H) 672.85.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:38]=[N:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1
Reactant: CC1(C)OB(c2cncc(C(F)(F)F)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cncc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 38.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (83 mg, 0.19 mmol) was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridine (130 mg, 0.47 mmol, prepared according to J. Aebi et al US 20090048238 19 Feb. 2009), sodium carbonate (2M, 350 μl, 0.70 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.02 mmol) according to the method described in Example 3 to give 37 mg (39% yield) of the title compound. Purity 99%.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10](=[CH2:13])[CH2:11]Br>>[Br:9][C:10](=[CH2:11])[CH2:13][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: Oc1ccccc1S
Reactant: C=C(Br)CBr
Product: C=C(Br)CSc1ccccc1O
Yield: 58 %

Procedure:
This compound was prepared from 2-mercaptophenol and 2-bromoallyl bromide in 58% yield according to the general procedure given for 16p in Example VII. Yellow oil; 1H NMR (CDCl3): δ 3.57 (s, 2H), 5.33 (d, J=14.55 Hz, 2H), 6.69 (d, J=2.50 Hz, 1H), 6.87, (t, J=7.40 Hz, 1H), 6.99 (d, J=8.25 Hz, 1H), 7.28 (t, J=7.70 Hz, 1H), 7.45 (d, J=7.70 Hz, 1H); 13C NMR (CDCl3): δ 47.63, 115.12, 120.39, 120.93, 124.92, 128.39, 131.89, 136.60, 157.56; HRMS (FAB): 243.9557 calcd for C9H9BrOS [M]+. found 243.9557.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14])=[O:4].[CH3:15][C:16]1[NH:20][CH2:19][CH2:18][N:17]=1>[N+](C)([O-])=O>[CH2:13]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3]([CH2:2][N:20]1[CH2:19][CH2:18][N:17]=[C:16]1[CH3:15])=[O:4])[CH3:14]
Reactant: CC1=NCCN1
Reactant: CCc1cccc(C)c1NC(=O)CCl
Solvent: C[N+](=O)[O-]
Product: CCc1cccc(C)c1NC(=O)CN1CCN=C1C

Procedure:
In a manner similar to Ex. IA react 21.17 gm. (0.1 M) of 2-chloro-2'-ethyl-6'-methylacetanilide and 42.1 gm. (0.5 M) of lysidine in 250 ml. of nitromethane, to obtain the title compound:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[C:4]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])[N:3]=1.[NH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:12]([NH:11][C:4]2[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=[C:2]([NH:21][C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[N:3]=2)[CH3:13])=[CH:15][CH:16]=1
Reactant: Nc1cnccn1
Reactant: CC(=O)c1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
150 mg of (S)-1-{2-chloro-6-[1-(4-fluorophenyl)ethylamino]pyridin-4-yl}ethanone, mg of 2-aminopyrazine, 49 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 59 mg of sodium t-butoxide and 23 mg of tris(dibenzylideneacetone)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 20 minutes under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 77 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino) pyridin-4-yl}ethanone. The obtained compound was subjected to hydrochlorination using a conventional method to obtain the objective compound as yellow powder.
Reaction SMILES: [CH:1]1([CH:4]([OH:6])[CH3:5])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:9]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][C:25](Cl)=[N:26][C:20]=2[O:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:9]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][C:25]([O:6][CH:4]([CH:1]3[CH2:3][CH2:2]3)[CH3:5])=[N:26][C:20]=2[O:19][CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Clc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CC(O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2)C1CC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
To a solution of 1-cyclopropylethanol (0.17 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of 4-benzyl-8-chloro-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.48 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(1-cyclopropylethoxy)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.42 g, 74%) as a yellow oil.