Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]=[O:37])[CH:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.[Cl-].[NH4+]>[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]([OH:37])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COc1cnc(C=O)cc1OC1CCCC1
Reactant: Cc1c(Cl)cncc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cnc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
n-Butyllithium (3.21 mL of 2.5 M solution) is added to a solution of diisopropylamine (1.15 mL) in dry tetrahydrofuran (25 mL) with the temperature being maintained below −60° C. After 30 min a solution of 3,5-dichloro-4-methylpyridine (1.21 g) in tetrahydrofuran (7 mL) is added dropwise and the mixture stirred for a further 30 min. A solution of 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g) in tetrahydrofuran (7 mL) is added and the mixture stirred for 4 hours whilst being allowed to warm to room temperature. After a further 18 hours at room temperature the mixture is diluted with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The extracts are washed with water, dried (MgSO4) and evaporated to give a yellow oil. The oil is triturated with n-pentane to give (±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol (1.4 g) as an off-white solid, m.p.110-112° C. [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.78, 6H, m; 1.95, 2H, m; 3.27, 2H, m; 3.79, 3H, s; 4.89, 2H, m; 5.64, 1H, d; 7.07, 1H, s; 7.98, 1H s; 8.54, 2H, s.].
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18]=[C:19]1O[C:21](=[O:22])[CH2:20]1>C(Cl)Cl>[CH2:1]([N:3]1[C:19]([CH3:18])=[CH:20][C:21](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCNC(=CC(=O)OCC)c1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(CC)c(C)cc1=O
Temperature: 25 °C

Procedure:
4.64 gms of ethyl beta-ethylamino-4-chlorocinnamate, 4.61 gms of technical grade diketene and 15 mls of methylene chloride are mixed in a flask fitted with a calcium chloride drying tube. The mixture is maintained at room temperature for 137 hours. The methylene chloride is removed in vacuo and the residue triturated with ether to yield 3.2 gms of crude ethyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate. mp (215-17).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[C:10]([CH:12]([C:28](OCC)=[O:29])[CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)#[N:11].C(O)(=O)C>C(O)C>[NH2:4][C:3]1[NH:5][C:28](=[O:29])[C:12]([CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:10]([NH2:11])[N:2]=1
Reactant: CCOC(=O)c1ccc(SCCCC(C#N)C(=O)OCC)cc1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1ccc(SCCCc2c(N)nc(N)[nH]c2=O)cc1
Yield: 95.6 %

Procedure:
Dry guanidine hydrochloride (3.43 g, 35.9 mmoles) was added to a solution of sodium ethoxide 53.5 mmoles) in ethanol (25 mL), and the mixture was treated with 1B (6.00 g, 17.9 mmoles) as a solution in ethanol (25 mL) and refluxed for 5 hours. After cooling, the pH was adjusted to 7.0 with acetic acid, and the mixture was evaporated to a viscous residue in vacuo. The residue was treated with water (70 mL) and was filtered to give an off white solid, which was washed with 3 volumes (30 mL) of water and 3 volumes (30 mL) of ether and was dried in vacuo to give crude product title compound, 1C, (5.96 g, 95%) as a white solid. NMR (DMSO-d6) δ1.3 (t, 3H, CH3 of ester), 1.65 (m, 2H, CH2 --CH2 --CH2), 2.3 (t, 2H, CH2 --CH2 --CH2 --S), 2.95 (m, 2H, CH2 --S), 4.3 (q, 2H, CH2 of ester), 5.7 (br s, 2H, NH2), 5.95 (br s, 2H, NH2), 7.3 (d, 2H) (benzoate H's ortho to sulfur), 7.85 (d, 1H, 7.95 (d, 1H), 9.8 (br s, 1H, ring NH). The aromatic region of the NMR spectrum indicated slight impurities; compound 1C was used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][C:33]3[N:32]=[CH:31][C:40]4[C:35]([CH:34]=3)=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(=O)OC(C)(C)C
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Step 3C 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (700 mg, 1.68 mmol, 1 equiv), 2-chloroquinoline (1.1 g, 6.7 mmol, 4 equiv) were dissolved in DMF (20 mL) and added with and NaH (202 mg, 60% in oil, 5.04 mmol, 3 equiv). The mixture was heat to 100° C. for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with sat. NH4Cl (aq). After stirring for 0.5 h, solid precipitated from the mixture. Solid was collected by filtration and washed with water and dried overnight to produce 793 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 87% yield.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:35]=[C:33]1[C:32]2[C:31](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:30](=[O:40])[N:34]1[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Diisopropyl azodicarboxylate (1.17 mL, 6.04 mmol) was added to a THF (15 mL) solution of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.64 mmol), phthalimide (888 mg, 6.04 mmol), and triphenylphosphine (1.58 g, 6.04 mmol), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography to obtain the target (1.45 g, 90%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH2:10][CH:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])O[N:7]=1.C[OH:20]>O=[Pt]=O>[C:14]([O:13][C:11](=[O:12])[CH2:9][CH2:10][CH:6]1[CH2:5][CH:4]([OH:20])[C:3](=[O:2])[NH:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CO
Reactant: COC(=O)CCC1=NOC(C(=O)OC(C)(C)C)C1
Agent: O=[Pt]=O
Product: CC(C)(C)OC(=O)CCC1CC(O)C(=O)N1

Procedure:
A suspension of 40 g of 4,5-dihydro-5-t-butoxycarbonyl-3-isoxazole-propanoic acid methyl ester and 2.0 g of PtO2 /C in 400 ml of methanol is placed under a hydrogen atmosphere with agitation. After H2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is triturated with anhydrous diethyl ether to yield 4-hydroxy-5-oxo-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 94°-95° C. NMR (CDCl3) and 6.83 (s, 1H, 4.42 (m, 1H), 3.93 (s, 1H), 3.70 (m, 1H), 2.78-1.66 (m, 6H), 1.47 (s, 9H). IR (KBr) 3320, 2980, 1732, 1705, 1456, 1417, 1353, 1368, 1295, 1260, 1214.
Reaction SMILES: [CH3:1][CH:2]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:37]C(OC)=O)[CH2:23][C@@H:24]2[O:32]C(OC)=O)=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH2:3]S(C1C=CC=CC=1)(=O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:52](Br)[CH2:53][CH:54]([CH3:56])[CH3:55].O>O1CCCC1>[CH3:55][CH:54]([CH2:53][CH2:52][CH2:3][C@H:2]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([OH:37])[CH2:23][C@@H:24]2[OH:32])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH3:1])[CH3:56]
Reactant: CC(C)CCBr
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
In 1 ml of tetrahydrofuran was dissolved 35 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene and the solution was cooled to -70° C. To the solution was added 0.8 ml of 0.1N solution of lithium hexamethyldisilazide in tetrahydrofuran. The resulting mixture was stirred for 30 minutes. After addition of 30 mg of isoamyl bromide, the mixture was stirred for 4 hours while the temperature was gradually raised to room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with an aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride, then dried over sodium sulfate and concentrated. The residue was dissolved in 1 ml of methanol and treated with 500 mg of 6% sodium amalgam in the presence of 0.5 ml of disodium hydrogen phosphate at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was dissolved in 1 ml of methanol, 10 mg of potassium carbonate was added, and the mixture was stirred for 12 hours. The reaction mixture was then subjected to the isolation and purification procedure of Reference Example 8 to give 15 mg of cholesta-5,7-diene-1α,3β-diol which showed the same 1H NMR spectrum as that obtained in Reference Example 8.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:28][C@H:27]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:14]([O:13][C:12]([NH:11][C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][NH:1][CH2:28][C@H:27]([NH:26][C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1

Procedure:
The product from Example 70C and the product from Example 70A were processed as described in Example 1D to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22](=O)[O:23]C2C=CC=CC=2)[CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=2)=[O:23])[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 164.9 %

Procedure:
To a stirred solution of 3-methyl-4-nitroaniline (566 mg, 3.7 mmol) in THF (10 mL) was added phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.0 g, 3.7 mmol), DIEA (972 mL, 5.6 mmol), and DMAP (50 mg, 0.41 mmol). The resulting mixture was refluxed for 60 h. The reaction mixture was then cooled to rt, partitioned between EtOAc (50 mL) and 3N HCl (15 mL). The organic layer was washed with sat. NaHCO3 (15 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford crude 1-(5-tert-butylisoxazol-3-yl)-3-(3-methyl-4-nitrophenyl)urea (2.0 g, 6.1 mmol). LC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH2:23][CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: [H][H]
Reactant: CCCC(NC(=O)Cc1ccc(C=CC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)Cc1ccc(CCC(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
A solution of of ethyl 2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-cinnamate (0.54 g, 1.1 mmol) in ethanol (15 ml) is hydrogenated for 1 hour at ambient temperature and under 3 bars of hydrogen on 10% palladium/charcoal (0.1 g). The mixture is filtered, concentrated by evaporation in vacuo and the evaporation residue is crystallized from petroleum ether.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])([CH3:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:25][C:18]([NH:26][C:27](=[O:31])[CH2:28][CH2:29][NH:30][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NC(=O)CCN)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCNC(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
0.3 g of benzoyl chloride was slowly dropped onto 10 ml of a toluene solution containing 0.4 g of N-(α,α-dimethylbenzyl)-3-aminopropionamide (prepared as described in Preparation 3) and 0.22 g of triethylamine. The reaction solution was then stirred for 2 hours, and, after dilution with 20 ml of diethyl ether, was washed with water and dried over anhydrous sodium sulfate. The reaction solution was then concentrated by evaporation under reduced pressure, and purified by silica gel chromatography, to give 0.52 g (yield 87%) of the title compound melting at 147°-148° C.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:61][CH2:60][CH2:59][CH2:58]4)=[C:49]([CH:53]=3)[C:50]([OH:52])=O)=[N:41][CH:42]=2)=[CH:33][CH:32]=1.CN>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[C:44][C:45]3[CH:46]=[CH:47][C:48]([O:54][CH2:55][CH2:56][N:57]4[CH2:58][CH2:59][CH2:60][CH2:61]4)=[C:49]([CH:53]=3)[C:50]([NH:2][CH3:1])=[O:52])=[N:41][CH:42]=2)=[CH:35][CH:36]=1
Reactant: O=C(O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
80 mg (0.25 mmol) TBTU and 69 μL triethylamine are added to a solution of 112 mg (0.25 mmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid (Example 22) in 5 mL DMF and the reaction mixture is stirred for 2 h at RT. Then 31 mg (1.0 mmol) methylamine are added and stirring is continued for a further 2 h at RT. The mixture is evaporated down i. vac., the residue is combined with dilute Na2CO3 solution, extracted exhaustively with DCM and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, DCM to DCM/MeOH/NH3 7:3:0.3).
Reaction SMILES: [NH2:1][C:2]([CH:16]([O:18][CH3:19])[CH3:17])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].FC(F)(F)C(O)=O.[CH3:27][C:28]1([CH3:36])[CH2:33][C:32](=O)[CH2:31][C:30](=[O:35])[CH2:29]1.[CH:37]1([CH:42]=O)[CH2:41][CH2:40][CH2:39][CH2:38]1>C(OC(C)C)(C)C>[CH:37]1([CH:42]2[C:31]3[C:30](=[O:35])[CH2:29][C:28]([CH3:27])([CH3:36])[CH2:33][C:32]=3[NH:1][C:2]([CH:16]([O:18][CH3:19])[CH3:17])=[C:3]2[C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][CH:7]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COC(C)C(N)=CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=CC1CCCC1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C1=C(C(=O)c2ccc(C(F)(F)F)cc2)C(C2CCCC2)C2=C(CC(C)(C)CC2=O)N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8.0 g 3-Amino-4-methoxy-1-(4-trifluoromethyl-phenyl)-pent-2-en-1-one are dissolved in 150 ml of diisopropylether, 2.2 ml trifluoroacetic acid and 4.1 g 5,5-dimethyl-cyclohexane-1,3-dione are successively added and the mixture is stirred for 10 minutes at room temperature. Then 3.75 ml cyclopentanecarbaldehyde are added and the mixture is heated for 15 hours to reflux at a dean-stark trap. After cooling to room temperature the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethylacetate 95:5 to 60:40). The product thus obtained is triturated with diisopropylether.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][O:48]CC3C=CC=CC=3)[C@@H:36]([O:37]CC3C=CC=CC=3)[C@H:27]([O:28]CC3C=CC=CC=3)[C@H:18]2[O:19]CC2C=CC=CC=2)[N:3]=1>C(O)C.O1CCCC1.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[N:4]([C@@H:17]2[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]2[OH:19])[N:3]=1
Reactant: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(C)nn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
The above tetrabenzyl compound 30 (294 mg) was dissolved in a mixture of ethanol (5 ml) and tetrahydrofuran (4 ml), and added thereto was palladium hydroxide (100 mg), and the mixture was stirred at room temperature for 16 hours under hydrogen atmosphere under normal pressure. Insoluble materials were filtered off, and the solvent was evaporated under reduced pressure. The residue was crystallized from diethyl ether to give the desired 3,5-dimethyl-4-(4-ethylphenylmethyl)-1-(β-D-glucopyranosyl)pyrazole 31 (118 mg) as colorless powder. APCI-Mass m/Z 377 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[NH4+].[Cl-]>C(O)C.O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([NH2:9])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)c(I)cc1N
Temperature: 60 °C
Reaction time: 40 h

Procedure:
To a mixture of 5-chloro-4-iodo-2-nitroaniline 1-5 (31.7 g, 106 mmol) and iron powder (59.0 g, 1060 mmol) in 880 mL ethanol was added a solution of NH4Cl (28 g, 530 mmol) in 240 mL of water. The resulting mixture was mechanically stirred at 60° C. for 40 h. After cooling to rt the mixture was filtered and the filtrate reduced to about 500 mL by rotary evaporation. This filtrate was diluted with 1 L of EtOAc and 1 L of water, and shaken. The organic layer separated, washed with brine, dried (MgSO4) and evaporated to provide crude product. The crude product was dissolved in 80 mL of EtOAc, diluted with 80 mL of hexanes and injected onto a 330 g column of SiO2, which was pre-eluted with 33% EtOAc in hexanes. The column was subjected to MPLC eluting at 100 mL/min with 33% EtOAc in hexanes (15 min) and then 50% EtOAc (20 min) to provide 5-chloro-4-iodo-1,2-phenylenediamine 1-6. Impure fractions of residue were resubjected to MPLC on a 330 g column of SiO2 by the same method to provide additional 5-chloro-4-iodo-1,2-phenylenediamine 1-6 as an amorphous solid. 1H NMR (500 MHz, DMSO-d6): δ 4.77 (s, 2H), 4.91 (s, 2H), 6.66 (s, 1H), 6.93 (s, 1H); LC-MS: calculated for C6H6ClIN2 267.9, observed Dole 269.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:65][N:66]1[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][N:66]5[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CCC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 7) (15 mg, 0.033 mmol, 1 eq), DIPEA (12 μl, 0.066 mmol, 2 eq) and TBTU (12 mg, 0.036 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (5 mg) and DIPEA (13 μL). The RM was then stirred at rt for 3 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide.