Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc(Br)cc1CO
Yield: 98.6 %

Procedure:
To 13 mmol of methyl 2-amino-5-bromobenzoate in 20 mL of THF at RT was added 65 mmol of 1M lithium tri-tert-butoxyaluminohydride over 10-15 minutes. The solution was heated at reflux for 17 hours. The solution was cooled, poured directly onto silica gel, and eluted with methylene chloride/ethyl acetate; 3:1 followed by 1:1. The product was eluted with 100% methanol to give 2.59 g of the title compound as an off-white solid. MH+: 202; LC: 1.09′.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6].[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].O>C(N(CC)CC)C.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>[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]
Reactant: C#CC(C)(C)C
Reactant: CC(=O)Nc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1ccccc1C#CC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h
Yield: 100.3 %

Procedure:
Under argon, 25.7 g (120 mmol) of ortho-bromoacetanilide, 5.05 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.37 g (7.2 mmol) of copper(I) iodide were initially charged in 450 ml of triethylamine. At room temperature, 17.8 g (180 mmol) of 3,3-dimethyl-1-butyne were then added dropwise over a period of 10 min, and the mixture is stirred at 50° C. for 5 h. The reaction mixture was poured into 2 l of water and extracted 3 times with in each case 250 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 with methylene chloride gave 25.9 g of N-[2-(3,3-dimethylbut-1-ynyl)-phenyl]acetamide of logP (pH 2.3)=3.03.
Reaction SMILES: [C:1]([N:8]1CCC(=O)CC1)(OC(C)(C)C)=O.[CH2:15]([NH:18][CH2:19][CH:20]=[CH2:21])[CH:16]=[CH2:17].[C-]#N.C([Al+]CC)C>ClCCCl.C1(C)C=CC=CC=1.C(Cl)Cl.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:15]([N:18]([C:1]#[N:8])[CH2:19][CH:20]=[CH2:21])[CH:16]=[CH2:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C=CCNCC=C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCN(C#N)CC=C
Temperature: 0 °C
Reaction time: 60 h
Yield: 175.3 %

Procedure:
To a solution of 1-Boc-4-piperidone (2.61 g, 13.03 mmol) in 1,2-dichloroethane (25 mL) was added diallyl amine (1.7 mL, 13.77 mmol) and the mixture cooled to 0° C. Titanium(IV) isopropoxide (3.9 mL, 13.3 mmol) was then added and the reaction warmed to room temperature and stirred for 2.5 d. The resultant orange mixture was then cooled to 0° C. and diethylaluminum cyanide added (1 M in toluene, 16 mL, 16 mmol) The reaction was warmed to room temperature, stirred for 3.5 h then diluted with CH2Cl2 (30 mL) and EtOAc (25 mL). The mixture was cooled to 0° C., quenched with water (7 mL) and filtered through celite, washing with CH2Cl2 and MeOH. The resultant filtrate was concentrated, diluted with CH2Cl2 (150 mL), dried (Na2SO4), concentrated and purified by flash chromatography on silica gel (Hexanes/EtOAc, 3:1 then 1:1) to afford the diallylamino-cyanide intermediate (2.79 g, 70%) as a yellow oil.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].O.[C:6]([OH:10])(=[O:9])[CH:7]=[O:8]>CC(C)=O>[C:1]([NH:4][CH:7]([OH:8])[C:6]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CC(N)=O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC(O)C(=O)O
Yield: 103.3 %

Procedure:
The titled compound 42 was prepared according to a procedure described by Williams et al.195 A solution of acetamide 34 (6.10 g, 0.10 mol) and glyoxylic acid monohydrate 41 (10.60 g, 0.14 mol) in anhydrous acetone (150 mL) was heated at reflux for 18 h. The reaction mixture was evaporated under reduced pressure to afford the desired product 42 as a viscous yellow oil (13.75 g, 100%). Spectroscopic data indicated the crude product 42 did not require purification and was used directly in the subsequent reaction (Section 7.9.2). νmax (neat): 3317bs, 2974w, 1732s, 1668s, 1538s, 1379m, 1234w, 1112w, 1048m, 880m cm−1. 1H n.m.r. (300 MHz, D6-DMSO): δ 1.84 (s, 3H, CH3CO), 5.39 (d, J=8.7 Hz, 1H, H2), (8.65, bd, J=8.4 Hz, 1H, NH), two exchangeable protons (OH) not observed. 13C n.m.r. (75 MHz, D6-DMSO): δ 22.5 (CH3CO), 70.9 (C2), 169.4 (CONH), 171.5 (C1). Mass Spectrum (ESI+, MeOH): m/z 134.2 (M+H)+, C4H8NO4 requires 134.1. Spectroscopic data were in agreement with those reported in the literature.195
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][CH2:12]O>S(=O)(=O)(O)O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[NH2:1])[CH3:12]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccnc1N
Yield: 74 %

Procedure:
A solution of 2-aminonicotinic acid (2.0 g, 14.4 mmol) in anhydrous EtOH (70 mL) and concentrated sulfuric acid (14 mL) was heated to reflux for 16 h. The solution was concentrated under reduced pressure, neutralized with saturated aqueous Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated to give 2-aminonicotinic acid ethyl ester as a yellow solid (1.74 g, 74%). 1H NMR (CDCl3) δ 1.40 (t, 3H, J=6.0 Hz), 4.34 (q, 2H, J=7.0 Hz), 6.41 (br s, 2H (NH2)), 6.63 (m, 1H), 8.14 (d, 1H, J=7.8 Hz), 8.22 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35]([CH:36]=O)[C:30]2=[CH:29][CH:28]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:35]3[C:30]4[C:31](=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=4)[NH:33][CH:34]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc2c(C=O)c[nH]c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.063 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 50° C. for 2 hours. The solid formed was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 81%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: NC1CCNC1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: NC1CCN(c2nccnc2OCCOc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0 53 mmol) and 3-aminopyrrolidine (247 mg. 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 123 mg (69%) of the title product. Anal. (C16H19Cl N4O2) H, N; C: calcd, 57.40; founds 56.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ester 12 (200 mg, 0.5633 mmol) in ethanol (0.7 ml) was treated at room temperature with 5% NaOH aqueous solution (0.45 ml). The resulting mixture was stirred at room temperature for 3 h. The ethanol was removed in vacuo and aqueous 5% HCl solution (0.46 ml) was added. The aqueous mixture was extracted with chloroform and the organic extracts dried (Na2SO4), filtered and the solvent removed under reduced pressure. The remaining white solid was recrystallized from chloroform as a white powder (133 mg, 72%). (Material that did not crystallize was collected by column chromatography using a gradient ethyl acetate to 50% MeOH in ethyl acetate). δH (400 MHz, MeOD) 4.65 (2H, s, CH2), 7.50 (2H, d, J=8.4 Hz, ArH), 7.70 (2H, d, J=8.4 Hz, ArH), 7.88 (2H, d, J=8.4 Hz, ArH), 8.02 (2H, d, J=8.4 Hz, ArH); δc (100.6 MHz, MeOD) 65.2, 127.7, 128.6, 128.8, 129.1, 134.9, 135.0, 137.7, 145.7, 168.3; MS (ES+) 343.7 (100%, [M+H2O]+), 323.7 (5%, [M+H]+), (ion not detected in ES−).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:27]([OH:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: O=C(O)C1(CNOCc2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(CC1(C(=O)O)CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold solution of formic acid (15.3 mL, 0.4 mol) in dichloromethane (100 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.75 mL, 60 mmol). After 1 h, a solution of 1-(benzyloxyamino-methyl)-cyclohexanecarboxylic acid from Preparation 19 (4.41 mmol theoretical) in dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 18 h and was concentrated in vacuo. Brine (100 mL) was added and the mixture was extracted with dichloromethane (100 mL×2). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale, orange oil (1.77 g, 100%). MH+292.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:9][SH:10])[N:3]=1>CO>[CH2:11]([N:7]([CH2:8][CH2:9][S:10][S:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[N:3]=[C:2]([NH2:1])[NH:6][N:5]=1)[C:4]1[N:3]=[C:2]([NH2:1])[NH:6][N:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc(N(CCS)Cc2ccccc2)n[nH]1
Solvent: CO
Product: Nc1nc(N(CCSSCCN(Cc2ccccc2)c2n[nH]c(N)n2)Cc2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
A mixture of 1.0 g of 5-amino-3-[N-(2-mercaptoethyl)benzylamino]-1,2,4-triazole, 20 ml of methanol and 5 mg of ferrous sulfate heptahydrate was stirred at room temperature for 16 hours. After the reaction, the resulting crystals were collected by filtration to give 0.9 g of bis{2-[N-benzyl-N-(5-amino-1,2,4-triazol-3-yl) amino]ethyl}disulfide (Compound 7).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[O:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[Sn]([N:28]=[N+:29]=[N-:30])(C)(C)C.[OH-].[Na+].CCCCCC>C1(C)C=CC=CC=1.O>[NH:28]1[C:1]([CH2:3][C:4]2[CH:5]=[C:6]([NH:10][C:11]([C:13]3[O:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[O:12])[CH:7]=[CH:8][CH:9]=2)=[N:2][N:30]=[N:29]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CCc1cccc(NC(=O)c2ccc(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=C(Nc1cccc(Cc2nnn[nH]2)c1)c1ccc(-c2ccccc2)o1
Reaction time: 0.17 h

Procedure:
To a solution of 5-phenyl-furan-2-carboxylic acid (3-cyanomethyl-phenyl)-amide (70 mg, 0.23 mmol) in toluene (3 ml) was added Me3SnN3 (56 mg, 0.28 mmol). After heating to reflux for 18 h, additional Me3SnN3 (56 mg, 0.28 mmol) and toluene (2 ml) were added and the reaction was heated to reflux for a further 18 h. After this time, 2M NaOH (2 ml) and hexane (2 ml) were added to the reaction mixture and stirred for 10 min. Water (1 ml) was added and the organic layer separated. EtOAc (2 ml) was added to the aqueous layer and the solution stirred for 2 min before the organic layer was separated. The combined organic layers were discarded. The aqueous layer was then acidified to pH 5 with 2M HCl then EtOAc (2.5 ml) was added and the solution stirred for 10 min after which time the organic layer was separated. EtOAc (2.5 ml) was added to the aqueous layer and the solution stirred for 1 hour. The EtOAc layer was separated and these combined organic layers were evaporated in vacuo to give the title compound.
Reaction SMILES: COC(=O)NC1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]6[NH:43][C:44]([CH:47]7[CH2:51][CH2:50][CH2:49][N:48]7[C:52](=[O:62])[CH:53]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]([CH3:56])[CH3:55])=[N:45][CH:46]=6)[CH:38]=5)[CH:33]=4)=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[O:15])CC2C(=CC=CC=2)C1.N[C:65]1(C(O)=O)[CH2:73][C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH2:66]1>>[CH3:61][O:60][C:58](=[O:59])[NH:57][C:73]1([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[C:21]2[NH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:42]6[NH:43][C:44]([CH:47]7[CH2:51][CH2:50][CH2:49][N:48]7[C:52](=[O:62])[CH:53]([NH:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]([CH3:56])[CH3:55])=[N:45][CH:46]=6)[CH:38]=5)[CH:33]=4)=[CH:28][CH:27]=3)=[CH:24][N:25]=2)=[O:15])[C:72]2[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=2)[CH2:66][CH2:65]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C6(NC(=O)OC)Cc7ccccc7C6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C6(NC(=O)OC)CCc7ccccc76)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 38 %

Procedure:
[1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-1-yl]-carbamic acid methyl ester (0.13 g, 38%) was prepared following the procedure for [2-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-indan-2-yl]-carbamic acid methyl ester, substituting 1-Amino-indan-1-carboxylic acid for 2-Amino-indan-2-carboxylic acid. LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.91 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:35]([O:37]C(C)(C)C)=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2].FC(F)(F)C(O)=O.ClCCl.CO.O.C(O)(=O)C.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([C:3]1[C:4]([NH:25][CH2:26][C@@H:27]([C:35]([OH:37])=[O:36])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH2:21][NH:22]3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCc1c(NC[C@H](Nc2ccccn2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1c(NC[C@H](Nc2ccccn2)C(=O)O)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 76 %

Procedure:
13 mg (0.023 mmole) of (1,1-dimethylethyl) 3-[[5-ethyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-4-pyrimidinyl]amino]-N-(2-pyridinyl)alaninate in 2 ml of dichloromethane with 0.2 ml of trifluoroacetic acid is stirred at ambient temperature until the starting product disappears according to TLC (silicagel, eluent: CH2Cl2-MeOH—H2O—AcOH 90-10-1-1). Toluene is added and the reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is solubilized in the minimum amount of dichloromethane then poured into diisopropyl ether. The precipitate is filtered. 13 mg (Yield=76% expressed as ditrifluoroacetate) of expected product is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH:8]=[O:9])[CH2:5][CH2:4][O:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(C=O)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CC(CO)CCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
To a solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (2.50 g) in methanol (15 mL) was slowly added at 0° C. sodium tetrahydroborate (3.30 g) by small portions, and the mixture was stirred at room temperature for 6 hr. The solvent was evaporated under reduced pressure, and saturated brine was added to the residue. The reaction mixture was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.50 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:31][CH2:30][O:29][CH:28]1[C:32]1[O:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=1.O1CCOC1.C(OC1C=CC(NC2C3C=C(C4OC(C=O)=CC=4)N=CC=3N=CN=2)=CC=1)C1C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:35]4[O:36][C:32]([CH:28]5[O:29][CH2:30][CH2:31][O:27]5)=[CH:33][CH:34]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Agent: Cl[Pd]Cl
Agent: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1COCO1
Product: c1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1

Procedure:
Reaction of (4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)amine (5.44 g, 15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (10.4 g, 24.2 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic amount) in dioxane (150 ml) according to Procedure B, followed by purification by silica gel chromatography (eluted with 50-100% EtOAc/i-hexane), allowed the isolation of the dioxolane product (3.45 g, 7.40 mmol, 49%); δH [2H6]DMSO 10.28 (1H, s), 9.13 (1H, s), 8.69 (1H, s), 8.61 (1H, s), 7.71 (2H, d), 7.31-7.52 (5H, m), 7.14 (1H, d), 7.09 (2H, d), 6.77 (1H, d), 6.03 (1H, s), 5.15 (2H, s), 3.95-4.19 (4H, m). This could then be converted to 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (identical to that described above) using Procedure C.
Reaction SMILES: C([Si](C)(C)O[CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([CH:18]2[NH:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])=[CH:11][C:10]1=[O:46])(C)(C)C.Cl.O1CCC[CH2:51]1>>[O:46]=[C:10]1[CH:11]=[C:12]([NH:15][C:16]([CH:18]2[NH:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH:13]=[CH:14][N:9]1[CH2:8][CH2:7][CH3:51]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C1CCOC1
Agent: Cl
Product: CCCn1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl}-amide (0.1 g, 0.14 mmol) in tetrahydrofuran (3 mL) was added aqueous HCl solution (1N, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with water, brine, dried over Na2SO4, then concentrated. The residue was purified by chromatography (10-15% of MeOH in EtOAc) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-oxo-1-propyl-1,2-dihydro-pyridin-4-yl)-amide as a white solid (Yield, 12 mg, 14%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([O:10][CH3:11])[CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=2)=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1ccc(CCl)cn1
Reactant: COc1cc(Br)c(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cc(F)c(Br)cc2OC)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a stirred solution of 4-bromo-5-fluoro-2-methoxyphenol (2.82 g, 12.25 mmol) in N,N-dimethylformamide (50 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (2.50 g, 12.86 mmol) and potassium carbonate (5.08 g, 36.75 mmol). The reaction mixture was heated to 100° C. After 2 h, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (0-33% ethyl acetate/hexanes elute) afforded 2.76 g (66%) of 5-((4-bromo-5-fluoro-2-methoxyphenoxy)methyl)-2-methoxypyridine as an oil.
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=2)[CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:3]1.[H-].[Na+].C(OCC)C.[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=O>CN(C)C=O>[Cl:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:10]/[C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][S:2][CH:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=CCCCCCl
Reactant: c1ccc([P+](Cc2cccc(-c3ccsc3)c2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCC/C=C/c1cccc(-c2ccsc2)c1
Reaction time: 0.25 h

Procedure:
400 mg of 3-(3-thienyl)benzyl(triphenyl)phosphonium bromide was dissolved in 2 ml of dimethylformamide, and under ice cooling, 37 mg of 60% oily sodium hydride was added. The mixture was stirred for 15 minutes, and to this solution was added an ethyl ether solution (0.6 ml) of the foregoing aldehyde compound. The mixture was stirred overnight at room temperature, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [hexane/ethyl acetate=19/1] to give 123 mg of the captioned compound (a mixture of E:Z=1:1) as a pale yellow oil.