Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][C:33]=1[F:34])[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2([CH3:36])O.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][C:33]=1[F:34])[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[CH2:36]
Reactant: CC1(O)c2cc(Cl)ncc2Oc2cc(F)c(Br)cc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: C=C1c2cc(Cl)ncc2Oc2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridinium p-toluenesulfonate (0.023 g, 0.090 mmol) was added to a solution of 7-bromo-3-chloro-8-fluoro-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol (0.619 g, 1.796 mmol) in DCE (7.19 mL) at 65° C. After 1.5 hours, the reaction was judged complete by LC/MS analysis and the solution was allowed to cool to rt and was poured into saturated sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to afford 7-bromo-3-chloro-8-fluoro-5-methylene-5H-chromeno[2,3-c]pyridine which was used directly for the next reaction without further purification. MS m/z=327.9 [M+H].
Reaction SMILES: [C:1]([N:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:20]=[C:19]3[C:14]([C:15](=[O:29])[C:16]([C:24]([O:26]CC)=[O:25])=[CH:17][N:18]3[CH2:21][CH2:22][F:23])=[CH:13][C:12]=2[F:30])[CH2:7]1)C)(=O)C.O.C(O)C>Cl>[F:30][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:11]=1[N:8]1[CH2:9][CH2:10][CH:6]([NH:4][CH3:1])[CH2:7]1)[N:18]([CH2:21][CH2:22][F:23])[CH:17]=[C:16]([C:24]([OH:26])=[O:25])[C:15]2=[O:29]
Reactant: CCOC(=O)c1cn(CCF)c2nc(N3CCC(N(C)C(C)=O)C3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)C1
Yield: 65.9 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (26.7 g) obtained according to the Reference Example 2, 3-(N-acetyl-N-methylamino)pyrrolidine (15.5 g), triethylamine (10.0 ml), and ethanol (300 ml) was heated under reflux for one hour. The reaction mixture was concentrated to a half volume under reduced pressure. To the mixture was added water (200 ml), and the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 24.8 g of ethyl 7-[3-(N-acetyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 227°-229° C. A solution of the above ester (20.0 g) in 20% hydrochloric acid (120 ml) was heated under reflux for 3 hours. After the reaction was completed, water (60 ml) and ethanol (120 ml) were added to the reaction mixture, and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (800 ml) and the solution was treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of 27% aqueous ammonia. The crystals were collected by filtration, washed with water, and dried to give 11.0 g of the compound 4, m.p. 243°-245° C.
Reaction SMILES: NC([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=3)[C:11]2=[O:28])[CH2:6][CH2:5]1)=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:52])C.O>>[NH2:52][CH:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=3)[C:11]2=[O:28])[CH2:8][CH2:9]1
Reactant: CC#N
Reactant: COC(=O)CCCc1ccc(N2CCN(C3CCC(C(N)=O)CC3)C2=O)cc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: COC(=O)CCCc1ccc(N2CCN(C3CCC(N)CC3)C2=O)cc1

Procedure:
Prepared from 1-(4-aminocarbonyl-cyclohexyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-one by treating with [bis-(trifluoroacetoxy)iodo]benzene in acetonitrile/water at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24]C)=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@@H:34]([O:37]C(=O)C)[CH2:33]2)[CH:3]=1.O.[OH-].[Li+].C(O)=O>O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]2)[CH:3]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](OC(C)=O)C2)ccc2c1OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CC[C@@H](O)C2)ccc2c1OCc1occc1-2
Yield: 4.8 %

Procedure:
A mixture of methyl 7-{4-fluoro-2-[(Z)-3-((R)-3-acetoxypyrrolidin-1-yl)prop-1-enyl]benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 82, 0.092 g) and lithium hydroxide monohydrate (0.039 g) in water (2 mL) and dioxane (4 mL), was scaled in a microwave vial and irradiated in the microwave at 110° C. for 20 minutes. After cooling, the mixture was diluted with water (20 mL), acidified with formic acid to pH 4-5 and extracted into DCM. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC (C6 Ph) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 30-60%, to give 7-{4-fluoro-2-[(Z)-3-((R)-3-hydroxypyrrolidin-1-yl)-prop-1-enyl]-benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylic acid (0.004 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C3C=CC=CC=3C(OC(C)(C)C)=O)=CC=2)C(Cl)=C(CO)N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
This Step A compound can be prepared as described in Example 3, Step A except that 2-butyl-1-[(2'-{N-triphenylmethyltetrazol-5-yl}{1,1'-biphenyl}-4-yl)methyl]-4-chloro-1H-imidazole-5-methanol can be used as the starting material for the oxidation instead of 2-butyl-1-[(2'-t-butoxycarbonylbiphen-4-yl)methyl]-5-chloro-1H-imidazole-4-methanol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:37])[NH:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH3:27])([CH3:26])[CH3:25].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.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[CH3:23][N:22]1[C:18]([C:11](=[N:10][O:9][CH2:8][C:6]2[N:7]=[C:2]([N:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:29](=[O:37])[O:28][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:3]=[CH:4][CH:5]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[N:21]1
Reactant: Cn1nnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Reactant: CCCCCONC(=O)OC(C)(C)C
Agent: CC(C)(C)O[K]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCCCCON(C(=O)OC(C)(C)C)c1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
In a purged and dried vessel, N-[(6-bromopyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.536 mmol, 1 eq.) was dissolved in 3 ml of toluene and tert-butyl(pentyloxy)carbamate (0.217 g, 1.072 mmol 2 eq.) was added followed by Pddba2 (0.065 g, 0.113 mmol, 0.21 eq.) and BINAP (0.069 g, 0.113 mmol, 0.21 eq.). Then tBuOK (0.12 g, 1.07 mmol, 2 eq.) was added and the vessel purged with argon and sealed. The reaction was stirred at 90° C. for 24 h. The solvent was evaporated and residue taken in EtOAc, filtered through “celite”, washed with H2O, dried over MgSO4, and concentrated. The crude was purified by chromatography on silica gel to give tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}(pentyloxy)carbamate (0.115 g, 41%) as a viscous yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([Br:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.1 g, 4 mmol) and Cs2CO3 (1.56 g, 4.8 mmol) in DMF (8 mL) was added benzyl bromide (500 μL, 4.2 mmol). The mixture was stirred at room temperature for 4 h, diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent, the residue was purified by column chloromatography (0-5% EtOAc-Hexane) to yield 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, 94%). 1H NMR (400 MHz, CDCl3) 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, 5H), 5.22 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23](OCC2C=CC=CC=2)=O)[CH2:19][CH2:18]1.C(N(CC)CC)C>CN1C(=O)CCC1.CO>[Br:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Br)cn1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Br)CC1
Yield: 29.6 %

Procedure:
N-(5-Bromo-4-chloropyridin-2-yl)pivalamide (Synthesis 155-A) (1.08 g, 3.70 mmol), benzyl 4-aminopiperidine-1-carboxylate (1.736 g, 7.41 mmol), and triethylamine (1.041 mL, 7.41 mmol) in NMP (7.41 mL) in a sealed vial was heated to 210° C. by microwave irradiation for 1.5 hr. The cooled solution was diluted with MeOH and purified by ion exchange on Isolute SCX II acidic resin eluting with MeOH then 2M NH3 in MeOH. He basic fractions were combined and volatiles were removed in vacuo. The crude product was dissolved in dichloromethane and loaded onto a Biotage silica column. Flash column chromatography eluting with a gradient of EtOAc in hexanes gave N-(5-bromo-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (0.536 g, 1.095 mmol, 30%) as a clear glass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[O:18][CH2:19][O:20][CH3:21])[OH:9])[CH:7]=1.C([O-])(O)=O.[Na+]>O.C(Cl)Cl.[K+].[Br-].CC1(C)N([O])C(C)(C)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[N:13]=[C:12]([F:17])[C:11]=2[O:18][CH2:19][O:20][CH3:21])=[O:9])[CH:7]=1
Reactant: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: COCOc1c(C(=O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 102.4 %

Procedure:
A solution of KBr (65.1 g, 0.55 mol) in water (5.9 L) was added to a solution of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol (2157 g, 5.47 mol) in DCM (5.9 L). The resulting biphasic mixture was cooled to 5° C. TEMPO (8.6 g, 0.055 mol) was added and the reaction mixture was stirred for 5 min. A solution of NaHCO3 (106 g, 1.26 mol, 0.23 eq) in bleach (6170 mL, 6.01 mol, 1.1 eq) was added slowly keeping the internal temperature below 10° C. After the addition was completed, the organic phase was separated. The aqueous layer was extracted with DCM (4 L×2). The combined organic layers were washed with 5% aqueous solution of sodium metabisulfite (6 L×1), brine (3 L×1) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure to give 2200 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanone as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>ClCCl.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 25 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), methyl 3-bromopropionate (128 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the product (62 mg, 25%): 1H NMR (400 MHz, CDCl3); δ 1.48-1.77 (m, 6H), 2.22-2.36 (m, 1H), 2.52-2.57 (m, 2H), 2.68-2.71 (m, 1H), 2.84-2.97 (m, 2H), 3.09-3.16 (m, 1H), 3.66 (s, 3H), 3.91-3.94 (dd, 1H J1=4.4 Hz, J2=10.0 Hz), 4.02-4.06 (dd, 1H J1=5.2 Hz, J2=10.0 Hz), 6.86-6.96 (m, 5H), 7.23-7.26 (m, 3H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH2:39])O1>COCCOC.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(Cl)Cl>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Reactant: CSc1nc(Cl)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: CSc1nc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 32 %

Procedure:
Method 26 was followed using 6-chloro-N,N-di-BOC-2-(methyl-thio)pyrimidin-4-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (0.07M) at 90° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) afforded 6-(3-aminopyridin-4-yl)-N,N-di-BOC-2-(methyl-thio)pyrimidin-4-amine in 32% yield. LCMS (m/z): 434.2 (MH+); LC Rt=3.56 min.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]([N:19]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]([N:19]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(N(CC2CC2)S(C)(=O)=O)ccc1OC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
Methyl 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoate (6 g, 15.02 mmol) was dissolved in THF (50 ml); LiOH 2M (15.02 ml, 30.0 mmol) was added; and the mixture was stirred at RT for 24 hours. The volatiles were removed under vacuum, and the residue was dissolved in water, neutralized with HCl 1M (pH 6) and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated to dryness. The resulting crude was purified by flash chromatography on silica gel column (DCM:MeOH=10:0.5) affording 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)benzoic acid (3 g, 7.78 mmol, 51.8% yield, MS/ESI+ 407.9 [MNa]+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:22])[CH3:21]
Reactant: NCCCC1c2ccccc2C=Cc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCCCC1c2ccccc2C=Cc2ccccc21

Procedure:
A solution of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (0.75 g., 0.003 mole) in 5 ml. of dry pyridine is treated with 1 ml. of acetic anhydride and then heated to refluxing for 30 minutes. The cooled solution is poured into 100 ml. of water and the oil extracted into benzene. The benzene extract is washed with water, 3N hydrochloric acid, water, and evaporated to dryness under reduced pressure. The 5-(3-acetamidopropyl)-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oily residue weighing 0.87 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21].Cl[C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:21][C:3]1[CH:4]=[C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Cl)c2)C1
Reactant: Clc1ncc(C2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C4CC4)cn3)c(Cl)c2)C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
tert-Butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (70 mg), 2-chloro-5-cyclopropylpyrimidine (45.0 mg, CAS 166740-44-9) and cesium carbonate (109 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.77 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.95 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 16 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (48 mg, 50%) as a colourless amorphous solid. MS (ISP): 433.2 ([{37Cl}M+H]+), 431.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39](Cl)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.O>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CNC(=O)c1nnc2ccc(Cl)nn12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 70 °C
Yield: 35.8 %

Procedure:
1.58 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)glycine ethyl ester were dissolved in 15 ml of N,N-dimethylformamide; 1.68 ml of N-ethyldiisopropylamine was added, followed by stirring under heating at an external temperature of 70° C. for 5 hours. After cooling, water was added; the reaction mixture was extracted with tetrahydrofuran. After concentration under reduced pressure, the precipitated crystal was twice recrystallized from ethanol-tetrahydrofuran (1:1), collected by filtration, and dried, to yield 995 mg of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.CN(C=O)C>O>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Reaction time: 4 h
Yield: 3.9 %

Procedure:
A mixture of 1.0 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.11 g of potassium carbonate, 760 mg of 4-methoxybenzyl chloride and 20 ml of DMF was stirred at 70°-80° C. for 4 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from methanol gave 60 mg of 5-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 194°-196° C., colorless needles.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([O:28]CC)=[O:27])[CH2:23]4)[S:19][CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].CO.C(O)(=O)C>O1CCOCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH2:21][N:22]4[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]4)[S:19][CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CN(Cc2cc(-c3cc(-c4ccc(CC(C)C)cc4)no3)cs2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(-c2cc(-c3csc(CN4CC(C(=O)O)C4)c3)on2)cc1
Yield: 80.2 %

Procedure:
To a solution of ethyl 1-({4-[3-(4-isobutylphenyl)isoxazol-5-yl]-2-thienyl}methyl)azetidine-3-carboxylate (0.47 g, 1.1 mmol) that was obtained in Example 9 (9h) in 1,4-dioxane (15 ml) was added a 1N aqueous solution of sodium hydroxide (3.3 ml, 3.3 mmol) at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 30 minutes. After adding methanol (15 ml) and water (5 ml) to the reaction mixture, the resulting mixture was heated under stirring until the white solid precipitated was dissolved, and then acetic acid (0.19 ml, 3.3 mmol) was added. The white solid precipitated was collected by filtration using a Kiriyama funnel, washed with methanol and dried in vacuo to afford the title compound (0.35 g) in a yield of 78% as a white crystalline solid.