Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25].CCN(CC)CC>ClCCCl>[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([Cl:38])[CH:30]=1)[CH3:25]
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: CCOC(=O)Cc1ccc(N=C=O)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 11.1) was reacted with (3-chloro-4-isocyanato-phenyl)-acetic acid ethyl ester in 1,2-dichloroethane in the presence of Et3N (1.4 eq.) for 2 d under reflux conditions to give the title compound as brown gum. MS: m/e=565.3 [M+H+].
Reaction SMILES: [C:1]1([C:7]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([O:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][O:27][NH2:28])([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.CO>[C:1]1([C:7](=[N:28][O:27][CH2:26][CH2:25][NH:24][C:23](=[O:29])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])[C:9]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCON
Reactant: O=C(c1ccccc1)c1c[nH]c2cnccc12
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1c[nH]c2cnccc12
Yield: 89 %

Procedure:
tert-Butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methylene]amino]oxy]ethylcarbamate (429.2 mg, 89%) was prepared as a white foam using phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanone (Reference Example 8) and tert-butyl[2-(aminooxy)ethyl]carbamate following the procedure described for Example 104: Rf 0.42 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) δ1.38-1.39 (9H, s), 3.40-3.44 (2H, m), 3.17-3.20 (1H, t, J=5.7 Hz), 3.26-3.28 (1H, t, J=5.3 Hz), 6.50-6.80 (1H, m), 7.30-7.50 (5H, m), 7.86-8.32 (2H, m), 8.76 (1H, s); ESI MS m/z 381 [C21H24N4O3+H]+; HPLC (Method A) 96.8% (AUC), tR=17.7 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:28][C:23]1[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:13]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH3:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccnc1C=O
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(CCCCNC(=O)OC(C)(C)C)C(C)c1nccs1

Procedure:
Using General Procedure B: Reaction of [4-(1-thiazol-2-yl-ethylamino)-butyl]-carbamic acid tert-butyl ester and 3-methyl-2-pyridine carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave {4-[(3-methyl-pyridin-2-ylmethyl)-(1-thiazol-2-yl-ethyl)-amino]-butyl}-carbamic acid tert-butyl ester as an oil. 1H NMR (CDCl3) δ 1.25-1.41 (m, 2H), 1.43 (s, 9H), 1.45-1.53 (m, 2H), 1.55 (d, 3H, J=Hz), 2.47-2.52 (m, 5H), 2.98-3.04 (m, 2H), 3.83 (d, 1H, J=Hz), 4.00 (d, 1H, J=Hz), 4.11 (q, 1H, J=Hz), 4.53 (bs, 1H), 7.10 (dd, 1H, J=7.6, 4.8 Hz), 7.23 (d, 1H, J=3.3 Hz), 7.44 (d, 1H, J=6.8 Hz), 7.66 (d, 1H, J=3.3 Hz), 8.36 (dd, 1H, J=4.8, 1.1 Hz).
Reaction SMILES: C([NH:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH:14]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:13]=2[C:12]([CH3:29])=[C:11]([O:30][CH3:31])[C:10]=1[CH3:32])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:14]2[C:13]3[C:12]([CH3:29])=[C:11]([O:30][CH3:31])[C:10]([CH3:32])=[C:9]([NH2:8])[C:17]=3[O:16][C:15]2([CH3:19])[CH3:18])=[CH:21][CH:22]=1)([CH3:28])[CH3:27]
Reactant: COc1c(C)c(NCc2ccccc2)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1c(C)c(N)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 83 %

Procedure:
Using N-benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine obtained in Reference Example 95, the title compound was synthesized in the same manner as in Reference Example 30. Yield 83%. Melting point: 111-112° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[C:33]2[C:43]([F:44])=[CH:42][CH:41]=[C:40]([F:45])[C:34]=2[S:35][C:36]=1[C:37](Cl)=[O:38]>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:37]([C:36]2[S:35][C:34]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:33]=3[C:32]=2[Cl:31])=[O:38])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:19]=[CH:18][C:17]=2[O:28][CH3:29])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccncc2)cc1CNC1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccncc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
Amine (297) (156 mg, 0.38 mmol) was reacted with acid chloride 8 (110 mg, 0.42 mmol) using Method D to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1.CCN(CC)CC>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)=[O:1]
Reactant: COC(=O)C1CCCC(CO)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclo-hexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of m-cresol (Aldrich) (80 g, 0.74 mol) in dry CH2Cl2 (300 mL) was added pyridine (71 mL, 0.89 mol) and at 0° C. was added dropwise acetyl chloride (58 mL, 0.81 mol). The reaction mixture was stirred for 1 h and then diluted with more CH2Cl2. The organic phase was washed successively with HCl 1N (3×), brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give 108 g (97% ) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[N:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(CC)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(CC)nc3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-[3-(6-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M172) (214 mg, 0.374 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (167 mg, 98%).
Reaction SMILES: N1C=CC=CC=1.[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:28][CH2:27]4)[CH:25]=3)=[C:17]([NH2:20])[CH:18]=2)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@@H:11]1[CH3:35])(=[O:9])[CH3:8].[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([NH:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[C:21]1[CH:22]=[N:23][N:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=1)[N:13]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:12][C@H:11]([CH3:35])[N:10]2[C:7](=[O:9])[CH3:8])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (5.09 μL, 0.063 mmol) was added to a solution of isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.010 g, 0.025 mmol) in dichloromethane (200 μL). Acetic anhydride (3.56 μL, 0.038 mmol) was added, and the reaction stirred at rt for 18 h. The reaction mixture was concentrated and ethyl acetate was added. The solution was washed with 1 N aqueous HCl, and the organic phase was separated and concentrated. The residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-6-acetamido-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 440 [M+H]+.
Reaction SMILES: C(N=C=NC(C)C)(C)C.[CH3:10][Si:11]([CH3:36])([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:21][CH:22]=1.[CH2:37]([C@H:42]1[CH2:47][CH2:46][C@H:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)[CH2:38][CH2:39][CH2:40][CH3:41].CN(C1C=CC=CN=1)C>C(OCC)(=O)C>[CH3:36][Si:11]([CH3:10])([CH2:30][CH2:31][C:32]([F:35])([F:33])[F:34])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:48]([C@H:45]3[CH2:46][CH2:47][C@H:42]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:43][CH2:44]3)=[O:49])=[CH:25][CH:24]=2)=[N:19][CH:18]=1
Reactant: C[Si](C)(CCCCOc1cnc(-c2ccc(O)cc2)nc1)CCC(F)(F)F
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ncc(OCCCC[Si](C)(C)CCC(F)(F)F)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diisopropyl-carbodiimide (DIC) (0.0454 g, 0.360 mmol) in ethyl acetate (3.0 ml) was added dropwise to a stirred solution of compound 41 (0.119 g, 0.300 mmol), trans-4-pentylcyclohexanecarboxlic acid (0.0713 g, 0.369 mmol) and dimethylaminopyridine (DMAP) (3.66 mg, 0.03 mmol) in ethyl acetate (3.0 ml). The reaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to give a colorless solid, which recrystallized acetonitrile to yield colorless crystals.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16](Cl)=O)[CH3:13].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15]([C:16]1[O:1][N:2]=[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]=1)=[O:19])[CH3:13]
Reactant: CCOC(=O)C(=O)Cl
Reactant: N=C(Cc1ccccc1)NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(Cc2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-Hydroxy-2-phenyl-acetamidine (1 g, 6.7 mmol) in 7 mL ethyl acetate was added a solution of Chloro-oxo-acetic acid ethyl ester (1.5 g, 10.7 mmol) in 7 mL ethyl acetate at 0° C. The mixture was stirred for 1.5 h at room temperature and then heated to 80° C. for 2.5 h. The reaction mixture was treated with aq. NaHCO3-solution and extracted with ethyl acetate. The organic layers were dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40ml/min) to yield the title compound. LCMS (method A) RtA=1.938 min; [M+H]+=233.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[NH:33][CH:34]=[N:35]2>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH:20][C:31]1[N:39]=[CH:38][N:37]=[C:36]3[C:32]=1[N:33]=[CH:34][NH:35]3)[CH3:19])=[CH:7]2
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)s1
Temperature: 130 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethanamine (9 mg, 30 μmol) in 1-butanol (1.5 mL) was added huenig's base (6 μl, 35 μmol) and 6-chloropurine (5 mg, 30 μmol). The reaction was heated to 130° C. for 16 hours and then cooled to room temperature. The crude reaction mixture was purified by reverse phase HPLC (gradient: 20% water in acetonitrile to 85% water in acetonitrile) to give N-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.62 (1H, s), 8.05 (1H, s), 7.83-7.89 (2H, m), 7.53-7.57 (1H, m), 2.89 (3H, s), 1.83 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=423.1 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[H-].[Na+].[C:22](OCC)(=[O:24])[CH3:23]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]([C:22](=[O:24])[CH3:23])[C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(CC#N)cc1OCCOC
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(C(C#N)C(C)=O)cc1OCCOC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
To a suspension of (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.59 g, 2.2 mmol), and sodium hydride (40% oil dispersion, 270 mg, 6.7 mmol) in tetrahydrofuran (10 mL), was added ethyl acetate (1.1 mL, 11.1 mmol), and the resulting mixture was stirred at 60° C. for 1.5 hours. Then it was cooled to room temperature, and poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH of 2. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-(3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.57 g, 1.9 mmol, 86% yield), MS (EI) for C16H21NO5: 308 (MH+).
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C(N(CC)CC)C.[C:47](Cl)(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)[C:47](=[O:54])[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N(Cc1ccc(CNCc2ccccn2)cc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.6 %

Procedure:
To a pre-cooled (ice bath) solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (201 mg, 0.37 mmol) and triethylamine (80 μl, 0.55 mmol) in anhydrous CH2Cl2 (4 mL) was added a solution of benzoylchloride (54 μl, 0.46 mmol) in anhydrous CH2Cl2 (0.5 mL) and the reaction mixture was allowed to stir at room temperature for 18 hours and then concentrated. The residue was diluted with ethylacetate (300 mL), washed with sat. aqueous NaHCO3 then brine, dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH2Cl2) to give the desired amide (203 mg, 85%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:4]([OH:5])[CH:1]1[CH2:3][CH2:2]1
Reactant: Nc1ccccc1C(=O)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(O)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a solution of o-aminophenyl cyclopropyl ketone (7.78 g, 48.3 mmol) in tetrahydrofuran at 0° C. is added 29 mL of a 1.0M lithium aluminum hydride solution in tetrahydrofuran. The reaction mixture is stirred at 0° C. for 2 hours, warmed to and stirred at room temperature for 16 hours, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 30% to 50% ethyl acetate in hexanes solutions gives the title product as a yellow solid (5.02 g, 64%, mp 76°-79° C.) which is identified by 1HNMR and MS spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:28](=[O:29])[CH2:27][S:19](=[O:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: NCCO
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO
Yield: 80 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 33.5 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.627 mmol), and hydrazine anhydrous (0.026 mL, 0.836 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered, and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (31 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.49 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.12 (m, 1H), 2.25 (s, 3H), 3.16 (m, 1H), 3.48 (m, 1H), 4.49 (m, 2H), 4.74-4.99 (m, 1H), 7.11 (t, J=8.3 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.74 (d, J=3.0 Hz, 1H), 7.89 (d, J=10.1 Hz, 1H), 9.97 (d, J=12.4 Hz, 1H), 12.03 (m, 2H).
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:15][C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:20][CH:19]=2>C(#N)C>[N+:25]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:23]=1[CH:24]=[C:16]([CH3:15])[N:17]2[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:27])=[O:26]
Reactant: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Temperature: 60 °C

Procedure:
Water (4.5 ml), potassium carbonate (25.9 g, 187 mmol) and ethyl bromoacetate (20.8 ml, 188 mmol) were added sequentially to a suspension of 2-methyl-4-nitro-1H-indole (30 g, 170 mmol) in acetonitrile (225 ml) and the mixture heated at 60° C. for 16 hours. After allowing to cool to ambient temperature, water (225 ml) was added and the resulting mixture was broken up and then filtered. The solid was washed with water (2×75 ml), followed by IMS (2×75 ml) then dried in a vacuum oven to give (4-nitro-2-methyl-1H-indol-1-yl)-acetic acid, ethyl ester, 32.15 g (72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[N+:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1[N+](=O)[O-]

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-nitrobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-nitrobenzoyl chloride in a similar manner as described above to give an orange solid (39% yield). 1H-NMR (CDCl3): δ 8.73 (s, 1H), 8.08 (m, 1H), 7.68 (m, 1H), 7.60 (m, 2H), 7.54 (m, 1H), 7.29-7.21 (m, 2H), 6.15 (d, 1H), 5.42 (m, 1H), 2.69 (m, 2H), 2.33 (m, 1H), 1.96 (m, 3H); MS m/z 414 (M−1).