Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:14][C:15]([C:20](O)=[O:21])=[N:16]2)=[CH:11][CH:10]=1.C[N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[NH4+]>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]1[C:18]([F:19])=[C:17]2[C:12]([C:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:14][C:15]([C:20]([NH2:31])=[O:21])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
TEA (105 μl, 0.757 mmol) was added to a solution of 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylic acid 7-12 (100 mg, 0.252 mmol) and HATU (96 mg, 0.252 mmol) in DMF (1262 μl). Ammonium Hydroxide (50.5 μl, 0.757 mmol) was added and the reaction stirred for 15 min at rt. The reaction was quenched with aqueous sodium hydrogen carbonate (saturated) and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-100%) to afford 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxamide 7-13 (63 mg, 63% yield) as a white solid, LCMS shows the compound is 100% pure 1H NMR (500 MHz, CDCl3): δ 8.28 (1H, s), 8.14 (1H, s), 7.68 (1H, d, J=8.85 Hz), 7.54 (1H, dd, J=8.86, 6.65 Hz), 7.50-7.46 (2H, m), 7.25-7.20 (2H, m), 5.69 (1H, s), 4.99 (2H, s), 2.78 (4H, s). LRMS m/z (M+H)+ 396.2 found, 396.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=[O:4].[B].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:11][CH:12]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][CH2:13]2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(=O)N(CC2COc3ccccc3O2)C1
Agent: Cl
Agent: [B]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CCN(CC2COc3ccccc3O2)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution containing 300 mg (1.03 mmol) of 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester in dry tetrahydrofuran (4 mL) was cooled to 0° C. under nitrogen. After adding 4 mL of 1M BH3-tetrahydrofuran solution (4.12 mmol), the reaction mixture was allowed to warm to room temperature and it was stirred for 5 h. Decomposition of the boron complexes was effected by addition of 3 mL of methanol and 3 mL of 6 M HCl-solution followed by stirring the mixture at 40° C. for ½ h. Tetrahydrofuran was evaporated off under vacuum. The residue was dissolved in 50 mL of water and the pH of the solution was adjusted to 10 using 1M Na2CO3 solution. The water phase was extracted with ethyl acetate (3×25 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography (silica gel, heptane/ethyl acetate, 7:3).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([NH:5][CH:6]1[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:4].C(O)C.Cl[C:17]1[N:26]=[C:25]2[C:20]([C:21](=[O:34])[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][N:24]2[CH:27]=[CH2:28])=[CH:19][C:18]=1[F:35]>C(N(CC)CC)C>[F:35][C:18]1[CH:19]=[C:20]2[C:25](=[N:26][C:17]=1[N:8]1[CH2:9][CH2:10][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[CH2:7]1)[N:24]([CH:27]=[CH2:28])[CH:23]=[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:21]2=[O:34]
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)nc21
Reactant: O=C(NC1CCNC1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(N3CCC(NC(=O)C(F)(F)F)C3)nc21
Yield: 84.8 %

Procedure:
A mixture of 3-trifluoroacetylaminopyrrolidine (5.46 g), ethanol (60 ml) and triethylamine (3 g) was added to ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate (5.93 g) obtained according to Reference Example 1. The mixture was heated under reflux for one hour. After ice-cooling, the resulting crystals were collected by filtration and washed with ethanol. Recrystallization of the crude crystals from ethanol-chloroform gave 7.5 g of ethyl 6-fluoro-7-(3-trifluoroacetylamino-1-pyrrolidinyl)-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylate, m.p. 280°-282° C. A solution of the compound (4.4 g) thus obtained in 1 N sodium hydroxide (80 ml) was stirred for 2 hours at 60° C. At the same temperature the mixture was adjusted to pH 7-8 by addition of acetic acid. After ice-cooling, the resulting crystals were collected by filtration, washed with water, and dissolved in hot 10% acetic acid, followed by treating with charcoal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=C[CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(OC=1C1C=CC=CC=1)=[N:42]C=CC=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:20])[C:30]4[C:35]([O:28][C:27]=3[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:42][CH:33]=[CH:32][CH:31]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2ncccc12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ncccc4c3=O)cc2)CCC1
Yield: 66 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (46.7 mg, 66%) as a colourless gum. LCMS (Method A): RT=4.65 min, [M+Na]+=491.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([CH2:38][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:35][C:34]=2[CH:58]=1)#[N:29].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[CH:38][C:36]3[O:37][C:33]4[CH:32]=[CH:31][C:30]([C:28]#[N:29])=[CH:58][C:34]=4[CH:35]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Yield: 71.8 %

Procedure:
3.12 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate was dissolved in 100 ml of tetrahydrofuran, followed by the addition of 4.65 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride. To the thus prepared solution was added 400 mg of 60% sodium hydride. With stirring, to the resulting mixture was added dropwise 3 ml of ethanol, followed by stirring at room temperature for 1 hour. The resulting reaction solution was neutralized with 10% citric acid solution, extracted with ethyl acetate, and then dried to distill off the solvent. Thereafter, the residue thus obtained was subjected to silica gel column chromatography using a toluene/ethyl acetate mixture as an elution solvent, thereby obtaining 3.1 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)acrylate in the form of viscous oil as a mixture of E and Z forms. A portion of the thus obtained compound was separated into E and Z forms. E form (less polar):
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].C([O-])(=O)C.[Na+].[Cl-].[Cl-].[NH3+:22][CH2:23][CH:24]([NH+:31]1[CH2:36][CH2:35][C:34]([F:38])([F:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:38][C:34]1([F:37])[CH2:33][CH2:32][N:31]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][NH:22][CH2:12][C:4]2[C:3](=[O:14])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:36][CH2:35]1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: [NH3+]CC(c1ccccc1)[NH+]1CCC(F)(F)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c(CNCC(c2ccccc2)N2CCC(F)(F)CC2)cc2ccccc21
Reaction time: 1 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (35 mg, 0.187 mmol), sodium acetate (19.94 mg, 0.243 mmol), and 1-(2-ammonio-1-phenylethyl)-4,4-difluoropiperidinium dichloride (51.7 mg, 0.187 mmol) were combined in 1,2-dichloroethane (2 ml). Acetic acid (0.021 ml, 0.374 mmol) and sodium triacetoxyborohydride (119 mg, 0.561 mmol) were added and the reaction stirred for 1 hour. The reaction mixture was partitioned between CH2Cl2 and satd. bicarb, the aqueous portion extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The material was carried on without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]C(OCC2C=CC=CC=2)=O)=[C:16](I)[CH:15]=1)=O)C1C=CC=CC=1.[C:39]1([CH3:45])[CH:44]=[CH:43][CH:42]=CC=1.C1CCCC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CO.CCOC(C)=O.CCCCCC>[CH:42]1([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[OH:20])[CH2:13][C@@H:12]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[NH2:11])[CH2:43][CH2:44][CH2:39][CH2:45]1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OC(=O)OCc2ccccc2)c(I)c1)NC(=O)OCc1ccccc1
Agent: C1=CCCC1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(C2CCCC2)c1
Temperature: 110 °C
Yield: 93 %

Procedure:
A 300 mL Parr bomb was charged with 5.13 g of tert-butyl N-((benzyloxy)carbonyl)-4-O-((benzyloxy)carbonyl)-3-iodo-L-tyrosinate, 120 mL of toluene, 30 mL of cyclopentene and 0.49 g of tri-ortho-tolylphosphine. The solution was deoxygenated by bubbling nitrogen through for 10 min and was treated with 0.182 g of Pd(OAc)2 and 1.24 mL of Et3N. The bomb was flushed with nitrogen, sealed, and heated to 110° C. for 48 h. The vessel was cooled to RT, purged with nitrogen and opened. The reaction mixture was filtered to remove solids and the filtrate was concentrated in vacuo to dryness. The residue was dissolved in 200 mL of EtOAc and the solution was washed with water(4×100 mL), dried over anhydrous NaSO4 and concentrated to give a thick brown oil. Analysis by tlc (SiO2, 8:2 hexane:EtOAc) indicated two major components at Rf =0.50 and 0.40. The crude mixture was subjected to flash chromatography on silica gel (8:2 hexane:EtOAc). This afforded 2.0 g (43%) of the Rf =0.50 material identified as the bis(benzyloxycarbonyl) olefin mixture by 1H-NMR. In addition, 0.90 g (25%) of the Rf =0.40 material was obtained and was identified as the N-benzyloxycarbonyl olefin mixture resulting from loss of the O-benzyloxycarbonly group. The bis(benzyloxycarbonyl) olefin mixture (2.00 g) ws subjected to catalytic hydrogenation (45 psi) in the presence of 0.35 g of 10% Pd(C) in 70 mL of MeOH for 18 h. The crude product was purified by flash chromatography (SiO2, EtOAc) to give 0.99 g (93%) of tert-butyl 3-cyclopentyl-L-tyrosinate as a transparent glass. The N-Benzyloxycarbonyl olefin mixture (0.90 g) was similarly hydrogenated and purified to afford 0.52 g (83%) of tert-butyl 3-cyclopentyl-L-tyrosinate.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]4)=[CH:23][CH:22]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:43]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([CH2:20][C:21]5[CH:26]=[CH:25][C:24]([N:27]6[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]6)=[CH:23][CH:22]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Reactant: O=C1CN(c2ccc(Cn3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(Cn3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{-4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Br:31])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCOCC>[Br:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][N:12]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:14])=[O:15])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=1[C:3]([OH:32])=[O:2]
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1Br)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2Br)c2c(C)cc(C)cc2C(=O)O)cc1
Yield: 79.3 %

Procedure:
In the same manner as described in Example 109, 0.518 g (1.0 mmol) of the product of Example 106 provided 0.4 g (79%) of the desired carboxylic acid as a white solid after trituration with ether. Electrospray Mass Spec 504.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([NH:33]C(=O)OCC5C=CC=CC=5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1>C1COCC1.CO.[Pd]>[NH2:33][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][C:20]1([CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:12]4[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=4)[N:6]=3)=[O:16])[CH2:18][CH2:19]1)[CH2:31][C:30]2=[O:32]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(NC(=O)OCc4ccccc4)ccc2O3)nc2c(OC)cccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N)ccc2O3)nc2c(OC)cccc12

Procedure:
3.78 g of benzyl {1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}carbamate was dissolved in 20 mL of THF and 40 mL of MeOH, and hydrogenated on 10% Pd/C at room temperature. Pd/C was removed through filtration, and the filtrate was concentrated to obtain the intended compound. 1H-NMR (CDCl3) δ: 7.77 (1H, dd, J=8.5, 1.2 Hz), 7.47 (1H, t, J=8.0 Hz), 7.17 (1H, s), 7.15 (1H, d, J=2.9 Hz), 7.08 (1H, dd, J=7.8, 1.0 Hz), 6.91 (1H, dd, J=8.8, 2.9 Hz), 6.85 (1H, d, J=8.8 Hz), 4.56 (1H, d, J=13.2 Hz), 4.16-4.08 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.63-3.53 (3H, m), 3.34 (1H, td, J=12.8, 3.3 Hz), 2.76 (1H, d, J=16.5 Hz), 2.70 (1H, d, J=16.5 Hz), 2.20 (1H, dd, J=13.9, 2.7 Hz), 2.05 (1H, dd, J=13.9, 2.7 Hz), 1.88-1.78 (2H, m). MS [M+H]+=448.
Reaction SMILES: [Na].CO.C[O-].[Na+:6].[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:8][O-:7].[Na+:6].[CH3:12][CH:11]([CH2:16][CH3:17])[CH2:10][CH2:9][CH2:8][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCC(C)CCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
Sodium methylate was prepared by reacting sodium (2.3 g, 0.1 mol) with 100 ml anhydrous methanol. To the sodium methylate was added methyl 4-hydroxybenzoate (15.2 g, 0.1 mol). Excess methanol was removed under reduced pressure and toluene was added and removed under reduced pressure to remove any residual methanol. The solid residue was dissolved in 2:1 toluene-dimethylformamide and S-4-methylhexyl bromide (17.9 g, 0.1 mol) was added as a single portion and the mixture was refluxed for 1 day. The reaction product was cooled and washed 3 times with 100 ml water. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. This crude methyl S-4-(4-methylhexyloxy)benzoate was refluxed in 100 ml of 10% aqueous sodium hydroxide for 1 day. The reaction product was cooled to room temperature (25° C.) and acidified with concentrated aqueous HCl. The precipated solid was collected by filtration and washed several times with cool water. This material was purified by recrystallization from ethanol-water. S- 4-(4-Methylhexyloxy)benzoic acid (20 g, 85% yield) was obtained. NMR and MS were consistent for the product.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=C1)(C)C.[NH:30]1C=CC(B(O)O)=N1>>[NH:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[N:30]1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Reactant: OB(O)c1cc[nH]n1
Product: CCOC(=O)c1cn2cc(-c3cc[nH]n3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-3-boronic acid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[C:12]([NH2:26])[N:11]=2)=[CH:6][CH:5]=1>C1COCC1>[NH2:26][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH3:25])[N:13]=1
Reactant: COC(=O)c1ccc(-c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.3 g (6.4 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester using 9.6 mL (9.6 mmol) 1 N NaOH in 20 mL THF. The product precipitates and is isolated by filtration and is washed with water. Yield: 2.2 g (99%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O.C(N)(=O)C1C=CC=CC=1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=1[CH2:38][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:18]1=[O:17]
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: Nc1ccccc1F
Agent: NC(=O)c1ccccc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1F)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoroaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluorophenyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (57%) as a colorless solid: mp 195-197° C.; 1H NMR (300 MHz, DMSO-d6) δ10.37 (s, 1H), 7.75-7.59 (m, 2H), 7.51-7.35 (m, 2H), 7.34-7.11 (m, 6H), 7.00 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.19-5.00 (m, 2H), 4.85 (d, J=9.4 Hz, 1H), 4.70 (d, J=9.4 Hz, 1H), 4.47 (t, J=8.8 Hz, 2H), 2.93 (t, J=8.8 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 161.6, 161.2, 142.8, 135.8, 134.6, 132.7, 131.1, 129.1, 128.6, 127.8, 127.4, 127.3, 127.0, 126.0, 125.8, 124.8, 124.7, 124.2, 123.6, 120.9, 120.4, 119.6, 116.4, 116.2, 109.7, 92.9, 80.5, 72.6, 57.5, 41.4, 28.8; MS (ES+) m/z 529.2 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][NH:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:30](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:30][N:14]([CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:29][CH:28]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1CNCc1ccc(Oc2ccc(Br)cc2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Product: CN(Cc1ccc(Oc2ccc(Br)cc2)cc1)C[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 74.2 %

Procedure:
A solution of 1,1-dimethylethyl 2-[[[[4-(4-bromophenoxy)phenyl]methyl]amino]-methyl]-1-pyrrolidinecarboxylate (900 mg, 1.9 mmol) in dichloroethane (10 mL) was stirred as acetic acid (180 mg, 3 mmol), formaldehyde (37% solution in water) and sodium triacetoxyborohydride (508 mg, 2.4 mmol) were added. The reaction was stirred for 17 hours. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel using a mixture of ethyl acetate in hexane gave 0.67 g of 1,1-dimethylethyl (R)-2-[[methyl[[4-(4-bromophenoxy)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:17]#[N:18])[C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+].Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:17]#[N:18])[C:14]=1[O:15][CH3:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(C#N)c(OC)c(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C#N)cc(C(=O)O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Methyl 3-t-butyl-5-cyano-4-methoxybenzoate (1.48 g) was dissolved in methanol (20 ml), tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (753 mg) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution, 10% hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.18 g) as a pale yellow crystal.