Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26]#[N:27])[C:23]([C:28]#[N:29])=[CH:22][C:20]=3[N:21]=2)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:30]1[CH2:40]CN2C(=NCCC2)C[CH2:31]1.ICCC>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([CH2:31][CH2:30][CH3:40])[C:20]3[CH:22]=[C:23]([C:28]#[N:29])[C:24]([C:26]#[N:27])=[CH:25][C:19]=3[N:18]=2)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCCI
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3n2CCC)cc1
Reaction time: 0.03 h
Yield: 62.2 %

Procedure:
Following a reported procedure, a sample of 3 (265 mg, 0.70 mmol) in NMP (2.5 mL) was heated to 120° C. and treated with DBU (105 μL, 0.70 mmol). After stirring for 2 min, iodopropane (105 μL, 0.70 mmol) was added and the mixture was stirred for 15 min. A second dose of DBU (68 μL, 0.70 mmol), followed by iodopropane (68 μL, 0.70 mmol), was added, and 15 min later, a third identical round of DBU and iodopropane was again added. After the mixture was stirred for 15 min, the reaction mixture was allowed to cool and was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Some starting material was recovered (83 mg, 31%), and fractions containing the product were concentrated to give a colorless solid (183 mg, 62%): mp 132-134° C.; 1H NMR δ 0.92 (t, J=8.0 Hz, 3H), 1.82-1.93 (m, 2H), 2.52 (d, J=8.8 Hz, 6H), 4.31 (t, J=7.6 Hz, 2H), 4.98-5.09 (m, 6H), 5.50-5.63 (3H), 7.53 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 8.19 (s, 1H); 13C NMR δ 11.4, 23.5, 41.9, 44.1, 47.3, 108.5, 109.0, 116.7, 116.8, 118.5, 126.1, 126.4, 127.9, 129.2, 134.0, 137.9, 145.4, 149.9, 159.4; Anal. Calcd for C28H28N4: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.93; H, 6.73; N, 13.35.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=O.O.[NH2:19][NH2:20]>O>[F:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:20][N:19]=[C:4]2[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1
Reactant: NN
Reactant: CN1CCC(C(=O)c2cc(F)ccc2F)CC1
Solvent: O
Product: CN1CCC(c2n[nH]c3ccc(F)cc23)CC1
Yield: 22 %

Procedure:
A mixture of 4-(2,5-difluorobenzoyl)-1-methylpiperidine of Example 111 (38.5 g, 0.16 moles) and hydrazine monohydrate (79.5 g, 1.59 moles) was heated in an autoclave at 150° for 22 hours. The autoclave was cooled in an ice bath and then opened. The reaction mixture was poured into H2O, causing the product to crystallize. The product was collected and then recrystallized twice from toluene to yield 8.2 g (22%) of 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole, m.p. 202°-204°.
Reaction SMILES: O=C1C=C(C(O)=O)OC2C3C=CC=CC=3SCC1=2.COCC1C(=O)C2C[O+](=O)([O-])C3C=CC4CCCCC=4C=3C=2SC=1C(O)=O.[O:46]=[C:47]1[CH:52]=[C:51]([C:53]([OH:55])=[O:54])[NH:50][C:49]2[C:56]3[C:67]4[CH2:66][CH2:65][CH2:64][CH2:63][C:62]=4[CH:61]=[CH:60][C:57]=3[S:58][CH2:59][C:48]1=2>>[O:46]=[C:47]1[CH:52]=[C:51]([C:53]([OH:55])=[O:54])[NH:50][C:49]2[C:56]3[CH:67]=[C:66]4[C:61]([CH2:62][CH2:63][CH2:64][CH2:65]4)=[CH:60][C:57]=3[S:58][CH2:59][C:48]1=2
Reactant: O=C(O)c1cc(=O)c2c([nH]1)-c1c(ccc3c1CCCC3)SC2
Agent: O=C(O)c1cc(=O)c2c(o1)-c1ccccc1SC2
Product: O=C(O)c1cc(=O)c2c([nH]1)-c1cc3c(cc1SC2)CCCC3

Procedure:
In the same manner, by using an appropriate amine of formula R16NH2 but replacing 4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid with an equivalent amount of one of the 4-oxo-tetrahydro-4H,5H-naphtho[2,1-b] or [2,3-b ] or [1,2-b]thiopyrano[2,3-d]pyran-2-carboxylic acids (described in Example 79), 4-oxo-1,4,9,10,11,12-hexahydro-5H-naphtho[1',2' : 5,6)thiopyrano[4,3-b]pyridine-2-carboxylic acid (1;R3, R4, R5 and R15 = H, R1 and R2 together form a CH2CH2CH2CH2 chain, X = S and Y = NH), 4-oxo-1,4,8,9,10,11-hexahydro-5H-naphtho[2', 3' :5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid (I; R1, R4, R5 and R15 = H, R2 and R3 together form a CH2CH2CH2CH2 chain, X = S and Y = NH), 4-oxo-1,4,7,8,9,10,-hexahydro-5H-naphtho[2', 1': 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid (I; R1, R2, R5 and R15 = H, R3 and R4 together form a CH2CH2CH2CH2 chain, X = S and Y = NH), 1-ethyl-4-oxo-1,4,8,9,10,11-hexahydro-5H-naphtho[2', 3' : 5,6]thiopyrano[4,3-b]pyridine2-carboxylic acid-6,6-dioxide (I; R1, R4R5 and R15 = H, R2 and R3 together form a CH2CH2CH2CH2 chain, X = SO2 and Y = NC2H5) and 3-methoxymethyl-4-oxo-1,4,9,10,11,12-hexahydro-5H-naphtho[1', 2' : 5,6]thiopyrano[4,3-b]pyridine-2-carboxylic acid-6,6-dioxide (I; R3, R4 and R 15 = H, R1 and R2 together form a CH2CH2CH2CH2 chain, R5 = CH2OCH3, X = SO2 and Y = NH) are obtained respectively.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CN(C=O)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.O.C(O)C>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[N:7]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(Cl)n2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)n2)n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A mixture of 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]propan-2-yl]pyrimidine (480 mg, 1.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (378 mg, 1.73 mmol) and 2M aqueous sodium carbonate solution (2.8 mL, 5.60 mmol) in a mixture of DMF (2 mL), 1,2-dimethoxyethane (2 mL), ethanol (2 mL) and water (5 mL) was purged with nitrogen for 10 minutes prior to addition of bis(triphenylphosphine)palladium(II) chloride (54 mg, 0.08 mmol). The reaction mixture was heated to 85° C. and stirred at that temperature, under nitrogen for 3 hours. The reaction mixture was then cooled and partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (25 mL). Combined organic layers were washed with brine (50 mL), dried (MgSO4), filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (367 mg).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11]C)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br-].O.[CH2:17]1COCC1>>[CH3:17][CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C1CCOC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(CC)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diethyl methylmalonate (5.19 g) in 100 mL of THF was added NaH (1.2 g, 60%) at 0° C. in portions. The mixture was stirred at 0° C. for 10 min, and to this solution was then added the bromide intermediate (3.84 g) in one portion. The mixture was warmed to 23° C. and stirred for 1 h before the addition of water. The resulting mixture was extracted with ethyl acetate, concentrated and purified by Biotage (5-10% ethyl acetate in hexane) to give the diester containing some diethyl methyl malonate contaminant as a crude oil.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[C:14]([NH:24][CH2:25][C:26]([OH:28])=O)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[NH2:29][C@H:30]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[CH2:31][OH:32].S(=O)(=O)(O)O>C1C=CC=CC=1.CC(C)=O.O.O1CCOCC1.O1CCCC1>[C:14]([NH:24][CH2:25][C:26]([NH:29][C@H:30]([C@H:33]([C@@H:35]([C@@H:37]([CH2:39][OH:40])[OH:38])[OH:36])[OH:34])[CH2:31][OH:32])=[O:28])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: N[C@@H](CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCOC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.25 h

Procedure:
A mixture of 275 ml. of dry tetrahydrofuran and 275 ml. of dry dioxane was cooled to -5° and 12.88 ml. (9.35 g., 0.092 mole) of triethylamine, 8.74 ml. (9.96 g., 0.092 mole) of ethyl chloroformate and 19.23 g. (0.092 mole) of N-carbobenzyloxyglycine were added. The mixture was stirred for 15 min. at -5° and then a cold (0°-5°) solution of 16.65 g. (0.092 mole) of 2-amino-2-deoxy-D-glucitol in 40 ml. of water was added in one portion. The cooling bath was removed and the mixture was allowed to stir at ambient temperature for four hours. The solvent was evaporated in vacuum at 30°-40° and the residue was stirred overnight with 500 ml. of ethanol. Filtration furnished 30 g. of a solid. The solid was recrystallized from 700 ml. of methanol to give 21 g. of product. Tlc shows the product to be pure (silica gel plate--benzene/methyl ketone/88% formic acid 60:25:25--methanolic sulfuric acid development).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[CH2:15][C:13]1[CH:14]=[C:9]([O:7][CH2:3][C:4]#[C:5][CH3:6])[N:10]=[CH:11][N:12]=1
Reactant: CC#CCO
Reactant: Fc1cccc(F)c1Cc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2c(F)cccc2F)ncn1
Temperature: 25 °C
Yield: 105.3 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol were slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2,6-difluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.24 g of 4-(2,6-difluorobenzyl)-6-(2-butynyloxy)pyrimidine (the present compound (80)), m.p.: 57.6° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)=[N:7][CH:8]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2CCOC)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 133 mg (0.40 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example 101F]) and 95 mg (0.40 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 12 ml of acetonitrile was added 143 mg (0.44 mmol) cesium carbonate. The reaction mixture was stirred for 16 h at RT. The mixture was filtered, taken up in dichloromethane dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 9:1, to give 119 mg of the title compound as light yellow viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:35][CH2:34][CH:33]([CH:36]2[CH2:39][NH:38][CH2:37]2)[CH2:32][CH2:31]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:38]4[CH2:39][CH:36]([CH:33]5[CH2:34][CH2:35][O:30][CH2:31][CH2:32]5)[CH2:37]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: C1CC(C2CNC2)CCO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.10 g, 0.26 mmol), 3-(tetrahydropyran-4-yl)azetidine (0.050 g, 0.28 mmol) in DCE (2 mL), trimethoxymethane (0.277 mL, 2.6 mmol) and acetic acid (0.015 mL, 0.26 mmol) was stirred for 2 h at room temperature. Sodium triacetoxyborohydride (0.090 g, 0.43 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water, the organic phase was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc gradient 0:100 to 10:90) to give 325 as a yellow solid (0.072 g, 56%). LCMS (Method G): RT=6.14 min, [M+H]+ 517.2. 1H NMR (CDCl3, 400 MHz) δ 8.02-7.98 (m, 1 H); 7.78-7.73 (m, 1 H); 7.35-7.25 (m, 2 H); 4.40-4.32 (m, 4 H); 3.98 (dd, J=11.7, 4.3 Hz, 2 H); 3.89-3.86 (m, 9 H); 3.42-3.30 (m, 5 H); 1.67-1.64 (m, 4 H); 1.55 (d, J=11.7 Hz, 2 H); 1.48-1.39 (t, J=7.5 Hz, 3 H); 1.29-1.16 (m, 3 H)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:22]=[N:23][CH:24]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[CH:14][C:13]=1[F:21])=[O:4].[OH-].[Na+]>CO>[F:21][C:13]1[CH:14]=[C:15]([CH:18]2[CH2:19][CH2:20]2)[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:22]=[N:23][CH:24]=[C:8]2[CH:7]=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2cncn2c1Nc1ccc(C2CC2)cc1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a solution of 5-(2-fluoro-4-cyclopropylphenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (573 mg, 1.73 mmol) in methanol (20 mL) was added aqueous sodium hydroxide (10 mL, 1M, 10 mmol) and the reaction mixture stirred at 70° C. for 30 minutes. The reaction mixture was concentrated in vacuo to ˜20 mL volume and the resultant solution diluted with water (20 mL) and filtered. The filtrate was acidified to pH ˜1 by addition of aqueous hydrochloric acid (1M) causing a precipitate to form. The precipitate was collected by filtration and dried under vacuum at 45° C. to yield the title compound as a dark tan solid (476 mg, 87%). LCMS (Method B): RT=2.81 min, M+H+=318.
Reaction SMILES: [S:1](O)(=O)(=O)[CH3:2].[CH2:6]1[CH:15]2C([CH2:11][CH2:12][CH2:13][CH2:14]2)CC[NH:7]1>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[SH:1][C:2]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:6]#[N:7]
Reactant: C1CCC2CNCCC2C1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1S

Procedure:
Following the procedures for Example 22, Step C, decahydroisoquinoline mesylate from preparation 3 (102 mg, 0.28 mmol) in acetone (0.5 mL), potassium carbonate solid (38 mg, 0.28 mmol, twice) and 2-mercaptobenzonitrile (38 mg, 0.286 mmol, twice) gave, after flash chromatography (hexanes-ethyl acetate 2:1), the desired product as an oil (64 mg) in 57% yield.
Reaction SMILES: [CH:1](/[CH:5]=O)=[CH:2]\[CH:3]=[O:4].[S:7](=[O:10])([OH:9])[O-:8].[Na+:11]>>[S:7](=[O:8])([OH:10])[O-:9].[CH:3](=[O:4])[CH2:2][CH2:1][CH3:5].[Na+:11]
Reactant: O=C/C=C/C=O
Agent: O=S([O-])O
Agent: [Na+]
Product: CCCC=O

Procedure:
maleic dialdehyde bis-sodium bisulfite
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@@H:16]([C:28](=[O:44])[N:29]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH3:30])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].C(=O)([O-])O>ClCCl>[CH3:43][S:40]([NH:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][CH2:31][N:29]([CH3:30])[C:28](=[O:44])[C@H:16]([NH:14][CH3:13])[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)(=[O:42])=[O:41]
Reactant: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 78.4 %

Procedure:
At 0° C., trifluoroacetic acid (1.5 ml) was added to a solution of N-((1R)-1-(N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl-ester (245 mg, 0.45 mmol) in dichloromethane (1.5 ml). The reaction mixture was stirred for 1.75 h at 0° C. Dichloromethane (5 ml) and a saturated aqueous solution of sodium hydrogen carbonate (6 ml) were added successively. Solid soidum hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 155 mg of (2R)-N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([BH3-])#N.[Na+]>>[F:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1cccc(F)c1
Yield: 60 %

Procedure:
Reduction 3-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compounds 44-A and 44-B gave the title hydroxylamine as a clear oil (60% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.50 (3H, s, OCH3), 4.04 (2H, s, NCH2), 5.75 (1H, broad s, NH), 6.95–7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 130–131° C. (dec.). Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.10; H, 5.73; N, 7.38.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[CH2:9][O:10][C:6]=2[C:5]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:2].[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[CH:29]1.N1CCCCC1>CO>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:9]2\[O:10][C:6]3[C:5]([CH2:14][N:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]4)=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:29]1
Reactant: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl 4-[(6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.138 g, 0.367 mmol) in methanol (1.5 mL) was added with indole-3-carboxaldehyde (0.0553 g, 0.367 mmol) and piperidine (0.0250 g, 0.294 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-ethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.137 g, 74%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[N:54]=[C:55]=[O:56].C(N(CC)CC)C>ClC(Cl)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:55]([NH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[Cl:47])=[O:56])=[O:43]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)Nc2ccccc2Cl)s1
Reaction time: 4 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (7.40 g) was dissolved in dichloroethane (100 ml). 2-Chlorophenyl isocyanate (1.2 ml) and triethylamine (4.2 ml) were added under ice-cooling, and the mixture was stirred for 4 hours. Then, the reaction mixture was washed with water and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (developing solvent:chloroform -methanol) to give 4.50 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-N'-(2-chlorophenyl)urea as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:8][N:9]1[C:13]2[C:14]([CH2:18]C(OCC)=O)=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:24].BrC[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(N(C)C)=O>[CH3:31][O:30][C:26]1[CH:25]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:27]=1[O:28][CH3:29])[CH2:8][N:9]1[C:13]2[C:14]([CH2:18][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:24]
Reactant: CCOC(=O)CCBr
Reactant: CCOC(=O)Cc1cccc2[nH]c(=O)n(Cc3cc(OC)c(OC)c(OC)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1cccc2[nH]c(=O)n(Cc3cc(OC)c(OC)c(OC)c3)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (14.1 mmol, 0.56 g, 60% mineral oil) is dissolved in dimethylacetamide (10 ml). 1-(3,4,5-trimethoxybenzyl)-3-hydrobenzimidazol-2-one (9.1 mmol, 2.86 g) (example 10) in dimethylacetamide (10 ml) is added dropwise to the ice cooled solution which is stirred for 1 hour. Ethyl 3-bromopropionate (14.1 mmol, 1.79 ml, 2.53 g) in dimethyl-acetamide (5 ml) is added, and the mixture is stirred 24 hours at room temperature. The solution is added dropwise into ice (300 g), and the precipitate is filtered off, added to a 1:1 dichloromethane/water mixture and is extracted with dichloromethane (3×20 ml). The combined organic layers are dried with MgSO4, filtered and evaporated. Recrystallisation from ethyl acetate (5 ml) yields the title compound (R1=(CH2)2—C(O)—OEt, R2=3,4,5-trimethoxybenzyl, x=2, n=0).