Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([NH:27][C:28]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[O:29])=[N:26][C:20]3=[CH:19][C:18]=2[C:17]([CH3:37])([CH3:36])[C:16]1=[O:38])(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([NH:27][C:28](=[O:29])[C:30]4[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=4)=[N:26][C:20]3=[CH:19][C:18]=2[C:17]([CH3:37])([CH3:36])[C:16]1=[O:38]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CN1C(=O)C(C)(C)c2cc3nc(NC(=O)c4cccnc4)[nH]c3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)N(Cc2ccccc2N)c2cc3[nH]c(NC(=O)c4cccnc4)nc3cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.7 %

Procedure:
(2-{7,7-Dimethyl-6-oxo-2-[(pyridine-3-carbonyl)-amino]-6,7-dihydro-3H-imidazo[4,5-f]indol-5-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (33.2 mg) is dissolved in CH2Cl2 (4 ml) and TFA (1.5 ml). The mixture is stirred at RT for 0.5 h. Saturated K2CO3 solution is added and the aqueous layer is extracted with CH2Cl2. The organic layer is dried over MgSO4, evaporated to dryness and the residue is purified by RP-HPLC, eluted with MeCN/water to give the desired product (4,5 mg).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@@H:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1.ClCl>O=[Mn]=O>[O:1]1[C:5]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[CH:4][CH:3]=[N:2]1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3ccno3)ccc3c2[C@H](CN3)C1
Agent: O=[Mn]=O
Agent: ClCl
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4ccno4)c(c23)C1
Reaction time: 4 h
Yield: 50.2 %

Procedure:
A mixture of (-)(2aR,4S)-6-(5-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (253 mg, 0.8 mmol) and 1 g of MnO2 in 100 ml of CH2 Cl2 was sonicated at 50-55 KHz for four hours. The reaction mixture was warmed to reflux during the time period. After four hours, the reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The resulting residue was chromatographed (flash column, silica gel, EtOAc) to provide 130 mg of title product. Recrystallization from hexane gave 60 mg of purified title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([OH:11])[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([O:11][S:23]([CH3:22])(=[O:25])=[O:24])[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)c1ccc(C)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of hydroxy-(5-methyl-thiophen-2-yl)-acetic acid methyl ester (I265) (1.84 g, 9.89 mmol) in dry DCM, cooled at 0° C. under nitrogen atmosphere, N-ethyl-N-isopropylpropan-2-amine (2.54 mL, 14.8 mmol) and methanesulfonyl chloride (1.16 mL, 14.8 mmol) are added and the reaction is stirred at RT for 2 hours. DCM is added and the organic phase is washed with aq. NaHCO3, water and brine, dried over Na2SO4 and evaporated to obtain intermediate I268 as a dark brown oil (2.1 g, 80% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([NH2:18])[CH2:14][C:15]([CH3:17])=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C@:13]([CH2:14][C:15]([CH3:17])=[CH2:16])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:18][C:33]2=[O:35])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(N)(CCNC(C)c1ccc(Br)cc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reaction time: 3 h
Yield: 133.1 %

Procedure:
To a solution of N1-[1-(4-Bromo-phenyl)-ethyl]-5-methyl-3-phenyl-hex-5-ene-1,3-diamine (2.97 g, 0.007 mol) and Et3N (3.53 g, 0.035 mol) was added triphosgene (0.58 g, 0.002 mol) at 0° C. The resulting mixture was stirred for 3 h. The mixture was washed with water, the organic layer was separated, and concentrated to give the crude (R)-1-((S)-1-(4-bromophenyl)ethyl)-4-(2-methylallyl)-4-phenyltetrahydropyrimidin-2(1H)-one (1.1 g, 40%). which was purified by column chromatography. 1H NMR (CDCl3): δ=1.24 (s, 3H), 1.38 (m, 1H), 1.43 (d, 3H), 1.56 (m, 1H), 1.88 (m, 1H), 2.09 (m, 1H), 2.12 (m, 1H), 2.44 (m, 1H), 2.64 (m, 2H) 4.72 (s, 1H), 4.83 (s, 1H), 5.21 (s, 1H), 5.74 (m, 1H), 6.90 (m, 2H), 6.92-7.14 (m, 2H), 7.18-7.38 (m, 5H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=[CH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1.Cl.[NH2:28][C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:32]=[CH:31][C:30]=1[OH:48]>CN(C)C=O.ClCCl.N1C=CC=CC=1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:28][C:29]2[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][S:38]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[CH:32]=[CH:31][C:30]=2[OH:48])=[O:24])=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Reactant: Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1ccc(C=Cc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
At -78° C., oxalyl chloride (135 mg, 1.06 mmol) was added to a mixture of 4-[2-(2-benzothiazolyl)vinyl]benzoic acid (247 mg, 0.88 mmol), dimethylformamide (one drop) and dichloromethane (10 ml), and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. Under ice-cooling, the resulting compound was gradually added to a mixture of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol hydrochloride (320 mg, 0.88 mmol), pyridine (3 ml) and dichloromethane (10 ml), and the resulting mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was heated until reflux and then cooled. Then, the solid material formed was collected by filtration and dried under reduced pressure. Ethanol (10 ml) was added to the resulting solid material, and the mixture was heated until reflux and then cooled. The crystals formed were collected by filtration and dried under reduced pressure to give 4-[2-(2-benzothiazolyl)vinyl]-5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxybenzanilide (335 mg, 0.57 mmol, 65%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[N:4](COCC[Si](C)(C)C)[N:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[CH:16]([O:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH3:17])#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)(OC(C)(C)C)OC(C)(C)C.C(N(CC)CC)C>ClCCl.N.CO>[C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH:16]([O:18][CH2:19][C:20]3([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:17])[CH:8]=[C:9]([C:12]([F:14])([F:15])[F:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2]
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n(COCC[Si](C)(C)C)nc12
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(3-cyano-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (95 mg, 0.14 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 3 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was concentrated to afford a crude product which was dissolved in dichloromethane (3 mL), cooled to 0° C., and treated with di-tert-butyl carbonate (63 mg, 0.29 mmol) and triethylamine (30 μL, 0.22 mmol). After 1 h, the reaction was treated with a few drops of 2 M ammonia in methanol and concentrated. The residue was dissolved in ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel (15% ethyl acetate/hexanes) afforded 40 mg (53%). 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.38-7.46 (m, 3H), 7.31-7.33 (m, 3H), 4.70 (q, J=6.7 Hz, 1H), 4.46 (m, 2H), 3.78-3.79 (m, 2H), 3.55 (d, J=8.9 Hz, 1H), 3.35 (d, J=8.9 Hz, 1H), 2.98-3.12 (m, 2H), 2.08-2.40 (m, 2H), 1.68-1.87 (m, 2H), 1.46 (m, 3H), 1.43 (s, 9H). Mass spec.: 529.19 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH2:33])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>CN(C1C=CN=CC=1)C.O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][N:21]4[N:30]=[C:31]([NH:33][C:35](=[O:37])[CH3:36])[N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nc(N)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To the solution of 6-1 (100 mg, 0.22 mmol) and Et3 N (0.2 mL) DMAP (2 mg) in dioxane (2 mL) was added acetyl chloride (21 mg, 0.25 mmol) and the mixture was heated at 100° C. for 10 h. The mixture was diluted with 20 mL of DCM, the combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 64 mg of 6-3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][OH:18])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.FC(F)(F)S(O[Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])(=O)=O.O>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][O:18][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)[Si](OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of Intermediate 77a (233 mg, 0.931 mmol) and Et3N (0.195 mL, 1.40 mmol) in dry DCM (5 mL) at RT under N2, was added triisopropylsilyl trifluoromethanesulfonate (0.313 mL, 1.16 mmol) and the yellow solution stirred at RT for 30 min. Water (5 mL) was added and the mixture shaken. The aqueous was extracted with DCM (5 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave a yellow oil. FCC, using 1-5% MeOH in DCM, gave the title compound as a yellow oil (333 mg, 88%). LCMS (Method 3): Rt 5.23 min, m/z 407 [MH+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:16])[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]=2[CH3:12])[N:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+]>O.CO>[CH3:12][C:10]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]([CH3:16])=[C:6]2[C:11]=1[C:2]([O:18][CH3:17])=[CH:3][CH:4]=[N:5]2
Reactant: C[O-]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2c(Cl)ccnc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Reaction time: 21 h

Procedure:
In a flask is placed 4-chloro-5,8-dimethyl-6-nitroquinoline (1.52 g, 5.4 mmol) with sodium methoxide (2.27 g, 4.2 mmol) and methanol (25 mL). The mixture is refluxed under argon with stirring for 21 hours, diluted with water (100 mL) and methanol (50 mL) and extracted with dichloromethane (2×200 mL). The organic layer is dried over potassium carbonate, filtered and evaporated. The product is purified by flash chromatography (7/3 hexanes/ethyl acetate), yielding 5,8-dimethyl-4-methoxy-6-nitroquinoline.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([OH:20])=O)=[CH:15][C:14]=2[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]2>C1COCC1.C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([C:18]([NH:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:41]4)=[O:20])=[CH:15][C:14]=2[CH:21]=1
Reactant: O=C(O)c1cc2cc(CSSc3ccccn3)ccc2o1
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc(NC(=O)c3cc4cc(CSSc5ccccn5)ccc4o3)ccc2[nH]1
Reaction time: 8 h

Procedure:
A stirred solution of 15 (247 mg, 0.78 mmol) in 30 mL dry THF at room temperature under argon, was treated sequentially with solutions of dicyclohexylcarbodiimide (177 mg, 0.86 mmol) in 5 mL methylene chloride, 4-(dimethylamino)pyridine (29 mg, 0.23 mmol) in 2 mL methylene chloride, and 10 (200 mg, 0.86 mmol) in 5 mL methylene chloride. The reaction mixture was stirred overnight. Dicyclohexylurea was filtered from the reaction mixture, and the filtrate was washed with water, cold 0.1M HCl, saturated aqueous sodium bicarbonate, and water. The organic solution was dried over magnesium sulfate, filtered, and concentrated to give a dark oil. The crude product was further purified by chromatography on a silica gel column, eluting with ethyl acetate:hexanes to give 16 as an off-white solid: NMR (acetone-d6) δ 1.6 (s, 9H), δ 4.3 (s, 2H), δ 7.0-8.6 (m, 12H).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1>[Ni]>[CH2:2]1[CH2:1][CH:5]2[CH:4]([CH:2]3[CH2:1][CH:5]2[CH2:4][CH2:3]3)[CH2:3]1
Reactant: C1=CCC=C1
Agent: [Ni]
Product: C1CC2C3CCC(C3)C2C1

Procedure:
hydrogenating the endo dimer of cyclopentadiene containing a dispersed nickel hydrogenation catalyst to provide a crude endo-tetrahydrodicyclopentadiene derivative having a melting point of at least about 70° C,;
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])OC(C)(C)C.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(Cl)=O.Cl.O1CCOCC1>C(Cl)Cl>[ClH:22].[NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[Cl:22]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 500 mg, 2.497 mmol) in dry DCM (8.3 ml) was added triethylamine (1.74 ml, 12.48 mmol) and 2-chlorobenzoyl chloride (CAS number 609-65-4; 476 μl, 3.74 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The Boc protect intermediate was dissolved in 1,4-dioxane (8 ml) and to this was added HCl in 1,4-dioxane (4 M, 6.0 ml, 23.91 mmol). The reaction was stirred at room temperature for 17 hours and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([C:29](OCC)=[O:30])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:47]=[CH:46][C:18]2[C:19]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:20]([CH2:22][O:23][C:24]3[C:28]([CH2:29][OH:30])=[CH:27][N:26]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:25]=3)[O:21][C:17]=2[CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(COc3nn(-c4ccccc4)cc3CO)oc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a solution of ethyl 3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazole-4-carboxylate (0.60 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.055 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. Sodium sulfate decahydrate (0.46 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give [3-({6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methoxy)-1-phenyl-1H-pyrazol-4-yl]methanol as colorless crystals (0.45 g, yield 80%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO.C(N)CN>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4ccc(Cl)nc4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N#CCC(c1ccc(Cl)nc1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
3-(6-Chloropyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (prepared by methods analogous to those described for Example 61) (0.070 g, 0.00014 mol) in TFA (3.0 mL, 0.039 mol) and DCM (3.0 mL, 0.047 mol) was stirred at room temperature for 1 hour. Solvent was removed in vacuo, and the residue was dissolved in methanol (4.0 mL, 0.099 mol) and ethylenediamine (0.07 mL, 0.001 mol). The reaction mixture was stirred at room temperature overnight. Solvent was removed in vacuo, the crude product was purified by preparative HPLC eluting with an ACN; water gradient buffered with ammonium hydroxide to pH=10, to give 3-(6-chloropyridin-3-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a white powder (35 mg, 69%), LCMS (M+1)+: 350, 1H NMR (DMSO-d6)□ δ12.21 (b, 1H), 9.00 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.00 (m, 1H), 7.70 (m, 2H), 7.00 (s, 1H), 6.22 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H)
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:13]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.CC(O)C>C(Cl)Cl>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH:35]([N:1]4[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]5[C:13]6[CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=[CH:17][C:12]=6[O:11][N:10]=5)[CH2:2]4)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide (100 mg, 0.318 mmol) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone (69 mg, 0.318 mmol) in DCM (10 mL) was added TEA (55 μL, 0.382 mmol) and the resulting solution was stirred at RT for 30 minutes. Sodium triacetoxyborohydride (81 mg, 0.382 mmol) was then added and the reaction was and stirred at RT overnight. The reaction was dissolved into DCM/IPA (3:1) solution and washed with saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by column chromatography using EtOAc (A) and 7N NH3 in MeOH (B) (from 100% A to 10% B in A) to give the above products as white solids. The less polar isomer from the silica gel column was tested in vitro as described in Example 107.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@H:11]2[N:15]([C:16](=[O:35])[C@@H:17]([CH2:23][N:24]([CH:33]=[O:34])[O:25]CC3C=CC=CC=3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:14]=[CH:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@H:11]2[N:15]([C:16](=[O:35])[C@@H:17]([CH2:23][N:24]([CH:33]=[O:34])[OH:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:14]=[CH:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](CN(O)C=O)C(=O)N1N=CC[C@H]1C(=O)Nc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of (5S)—N-(5-fluoro-2-pyridinyl)-1-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-4,5-dihydro-1H-pyrazole-5-carboxamide (180 mg, 0.37 mmol) in methanol (15 mL) was added Pd(OH)2/C (105 mg, 20%, 44% wt). The mixture was stirred under a H2 atmosphere for 30 min and the catalyst was filtered off. The filtrate was concentrated and the residue was purified by HPLC to provide the titled compound (70 mg, 48%) as a white solid. LCMS: (M+H)+: 394.2.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1)#[N:31]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([S:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([S:38][C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=2)=[O:27])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCSc1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCSc1ccc(C(=O)Sc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (0.99 g, 0.005 mol), was added in one portion to a stirred solution of compound 2 (1.04 g, 0.005 mol), compound 10 (0.56 g, 0.004 mol) and 4-(dimethylamino)pyridine (0.20 g, 0.002 mol), in dry dichloromethane (50 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The product was extracted into ether (200 ml) and was washed with aqueous potassium hydroxide solution (5%, 2×250 ml). The ether layer was evaporated in vacuo and the product was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 1:1] and was recrystallised from ethanol to afford a white solid which was dried in vacuo (P2O5).