Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[OH:16].Cl[CH2:18][C:19](Cl)=[O:20].[H-].[Na+]>C1COCC1>[Br:15][C:13]1[CH:12]=[CH:11][C:10]2[O:16][CH2:18][C:19](=[O:20])[NH:8][C:9]=2[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 min then allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60% suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 min then at r.t. for 2 h before being quenched with water (20 mL). The THF was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered off, washed with water (3×50 mL) and dried in vacuo to yield the title compound as a beige solid (2.14 g, 70%). δH (DMSO-d6) 4.60 (2H, s), 6.92 (1H, d, J 8.5 Hz), 7.02 (1H, d, J 2.3 Hz), 7.08 (1H, dd, J 8.5, 2.3 Hz), 10.81 (1H, br s).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C:16]1([CH2:22][C:23]([NH2:25])=[NH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:22]([C:23]1[N:25]=[C:11]([OH:13])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)Cc1ccccc1
Product: CCOC(=O)c1cnc(Cc2ccccc2)nc1O
Yield: 40 %

Procedure:
The title compound was prepared by (a) reaction of diethyl ethoxymethylenemalonate (11 g, 52 mmol) with phenylacetamidine (8 g, 60 mmol) to afford 40% of ethyl 2-benzyl-4-hydroxypyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of 2-benzyl-4-hydroxypyrimidine-5-carboxylate (3 g, 12 mmol) with POCl3 (18 g, 116 mmol) to afford 45% of 2-benzyl-4-chloropyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of 2-benzyl-4-chloropyrimidine-5-carboxylate (1.5 g, 5.5 mmol) with hydrazine (0.5 g, 16 mmol) to afford 75% of 2-benzyl-4-hydrazinopyrinmidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 2-benzyl-4-hydrazinopyrimidine-5-carboxylate (1 g, 3.5 mmol) with citraconic anhydride (1 g, 11 mmol), in analogy to Example 21, to afford 70% (0.9 g) of the title compound; m.p. 117-118° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>[OH-].[Na+]>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCOCC1
Reactant: OCc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2-hydroxybenzyl alcohol (1.295 g, 10.4 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.94 g, 10.4 mmol) in 2N NaOH (10.5 mL) was stirred at rt for 14 hours. The precipitate was collected by vacuum filtration, washed with 1N NaOH, redissolved in DCM and washed with 1N NaOH. The aqueous layer was extracted with more DCM (2×). The combined DCM was dried and concentrated to give [2-(2-morpholin-4-yl-ethoxy)-phenyl]-methanol which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Product: COc1ccc(CNc2nccc(-c3c[nH]nc3-c3ccc(F)cc3)n2)cc1
Yield: 80 %

Procedure:
This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine, was obtained as a off-white solid in 80% yield, mp: 183–185° C.; Anal. Calc'd for C21H18FN5O: C, 67.19; H, 4.83; N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:39][CH2:38][C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)=[O:28])=[CH:30][CH:31]=3)[S:21][CH:22]=2)(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)O)cc3)n2)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2csc(-c3ccc(C(=O)NCc4cccnc4)cc3)n2)cc1
Yield: 68.3 %

Procedure:
Method E. Reaction of oxalyl chloride (70 λL, 0.8 mmol) and benzoic acid 53 (200 mg, 0.54 mmol) with subsequent reaction with 3-pyridinylmethylamine (60 λL, 0.6 mmol) gave benzamide 54 (171 mg, 68%) as a white powder: mp (EtOAc) 178-181° C.; 1H NMR δ 9.19 (t, J=5.9Hz, 1 H, CONH), 8.57 (d, J=1.6Hz, 1 H, H-2″), 8.47 (dd, J=4.8, 1.5Hz, 1 H, H-6″), 7.97 (dd, J=6.7, 1.8Hz, 2 H, H-2 , H-6), 7.81 (dd, J=6.7, 1.8Hz, 2 H, H-3, H-5), 7.74 (ddd J=8.1, 2.1, 1.6Hz, 1 H, H-4″), 7.68 (s, 1 H, H-5′), 7.65 (dd, J=8.3, 1.7Hz, 2 H, H-2″, H-6″), 7.41 (br d, J=8.3Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=8.1, 4.8, 0.7Hz, 1 H, H-5″), 4.87 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.40 (s, 3 H, CH3); 13C NMR δ 165.7, 165.5, 148.9, 148.1, 145.2, 144.3, 135.9, 135.3, 135.2, 135.0, 134.9, 129.5 (2), 128.2 (2), 128.1 (2), 125.9 (2), 123.4, 122.2, 57.0, 40.5, 21.0; MS m/z 464.8 (MH+, 100%). Anal. calcd for C24H21N3O3S2: C, 62.18; H, 4.57; N, 9.06. Found: C, 62.30; H, 4.55; N, 9.10%.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]([O:19]CC)=O)[CH2:6]1)(=[O:4])=[O:3].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>CCO.CO>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:17](=[O:19])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)N1CCc2c(cccc2OCC(=O)NCC(O)CN2CCc3ccccc3C2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
A mixture of ethyl 2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (140 mg, 0.447 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (184 mg, 0.89 mmol) in EtOH (0.2 mL) was stirred at 120° C. for 30 min under microwave conditions. The mixture was diluted with MeOH and purified by prep-HPLC to afford N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetamide (53.5 mg, 25%). 1H NMR (400 MHz, MeOD) δ 0.84 (s, 1H), 7.29-7.15 (m, 5H), 6.80 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.41 (s, 2H), 4.35-4.17 (m, 3H), 3.54 (t, J=6.1 Hz, 2H), 3.48-3.38 (m, 4H), 3.17-3.04 (m, 4H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (s, 3H). LCMS (m/z): 474.2 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([OH:51])=O)[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[C:53]1([CH:59]([N:66]2[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C=O)C>[CH:59]([N:66]1[CH2:71][CH2:70][N:69]([C:49]([C:47]2[N:48]=[C:43]3[CH2:42][CH2:41][CH:40]([C:36]4[CH:37]=[C:38]([CH3:39])[C:33]([O:32][CH3:31])=[C:34]([CH3:52])[CH:35]=4)[CH2:45][N:44]3[CH:46]=2)=[O:51])[CH2:68][CH2:67]1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(C(c5ccccc5)c5ccccc5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (212 mg; 0.66 mmol) and N-methylmorpholine (181 μl; 167 mg; 1.65 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (165 mg; 0.49 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then diphenylmethylpiperazine (166 mg; 0.7 mmol) was added. The reaction mixture was stirred for 4 h at room temperature and poured onto water. The precipitated solid was filtered. Yield: 232 mg (88%).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13][C:14]1[CH:18]=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20].O>ClCCl>[Br:13][C:14]1[C:18]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([CH3:19])[S:16][C:15]=1[CH3:20]
Reactant: Cc1cc(Br)c(C)s1
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Under a nitrogen atmosphere, ethyl chlorooxoacetate (1.04 mL, 9.27 mmol) and aluminum chloride (per 3 portions) (2.47 g, 18.54 mmol) was added successively at −5° C. to a solution of 3-bromo-2,5-dimethylthiophene (28b) (886 mg, 4.64 mmol) in dichloromethane (20 mL). After 3 hours at −5° C., the reaction mixture was slowly hydrolyzed at 0° C. with water. The organic layer was separated, washed with water, brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to give the desired keto-ester (28c) (725 mg, 2.50 mmol, 50%).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.[F:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]>>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:26])[CH:34]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)c(F)c3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt and 2,4-difluorobenzonitrile using procedures analogous to those for Example 14. Analytic LCMS (M+H)+: m/z=444.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To a mixture of 6-(4-aminophenoxy)-hexanoic acid methyl ester 17 (25 g, 105 mmol) and triethylamine (21.4 g, 211.6 mmol) in acetone (200 ml) at 0° C. was added dropwise benzyloxy acetyl chloride (25 g, 135.5 mmol) followed by stirring at room temp. for 12 hrs. The solids were filtered off, acetone distilled off and water (100 ml) added. Crude 53 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×100 ml), then water (100 ml), dried over sodium sulphate and distilled. Crude 53 was purified by column chromatography on silica gel using benzene as eluant to get pure 53 (9 g, 22.2%), an off-white powder with a m.p. between 46-49° C.
Reaction SMILES: [H-].[K+].[CH3:3]CCCCC.[OH:9][CH2:10][CH:11]1[C:20]23[CH2:21][CH2:22][CH:13]([CH:14]4[O:29][C:28]5[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:27]=5[C:15]42[CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]3=[O:23])[CH2:12]1.CI>O1CCCC1>[CH3:35][O:34][C:30]1[C:28]2[O:29][CH:14]3[CH:13]4[CH2:22][CH2:21][C:20]5([CH:11]([CH2:10][O:9][CH3:3])[CH2:12]4)[C:15]3([CH2:16][CH2:17][N:18]([CH2:24][CH2:25][CH3:26])[C:19]5=[O:23])[C:27]=2[CH:33]=[CH:32][CH:31]=1
Reactant: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(CO)C2
Reactant: CCCCCC
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCN1CCC23c4cccc(OC)c4OC2C2CCC3(C1=O)C(COC)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 9 g of 35% potassium hydride in oil, prewashed with hexane, and 40 mL of tetrahydrofuran was added 4.05 g of 5-hydroxymethyl-9-methoxy-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. The mixture was stirred at room temperature for 30 minutes, and then heated under reflux for 30 minutes. Methyl iodide (8 mL) was added to the cooled mixture which was then heated under reflux for one hour. Excess hydride was destroyed by addition of 10 mL of methanol, and the solvent was removed. The product was taken up in methylene chloride/water, and the aqueous layer was extracted with methylene chloride. Removal of the solvent gave 4.45 g of 9-methoxy-5-methoxymethyl-3-n-propyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. NMR spectrum (δ in CDCl3); 6.8 (m, 2H); 6.5 (m, 1H); 4.5 (s, 1H); 3.9 (s, 3H); 3.3 (s, 3H) and 1.0 (t, 3H), among others.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:19]([P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH:20]=[CH2:21].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:21][CH:20]([CH2:19][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(Cl)cc1
Reactant: C=CCP(=O)(OCC)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CC1CC(c2ccc(Cl)cc2)=NO1)OCC
Yield: 104.5 %

Procedure:
Preparation is carried out as in Example 1 from 23.34 g of 4-chlorobenzaldoxime, 22 g of N-chlorosuccinimide, 29.5 g of diethyl allylphosphonate and 22.9 ml of triethylamine in dichloromethane and provides 52 g of oily product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:13]1[S:21][C:20]2[C:19]([C:22]#[N:23])=[CH:18][N:17]=[C:16]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:15]=2[CH:14]=1>[Cu]I.O1CCOCC1>[N:1]1([C:13]2[S:21][C:20]3[C:19]([C:22]#[N:23])=[CH:18][N:17]=[C:16]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:15]=3[CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(I)cc23)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc(C#N)c3sc(-n4ccnc4)cc23)cc1
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To an oven dried Schlenk tube was added CuI (0.0057 g, 0.030 mmol), imidazole (0.097 g, 1.42 mmol), Cs2CO3 (0.405 g, 1.25 mmol). The tube was evacuated and purged to argon 5 times. Under argon, the tube was supplied with 2-iodo-4-(4-methoxybenzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27 (0.25 g, 0.59 mmol) trans-1,2-cyclohexanediamine (0.014 mL, 0.12 mmol), and dioxane (1 mL). The reaction contents were briefly evacuated and the vessel purged to argon 3 times, then sealed and brought to 110° C. with stirring. After 24 h, 20 mL of CH2Cl2 were added to the cooled reaction. The mixture was filtered and solvents removed in vacuo. Silica gel column chromatography (eluent: 3% MeOH in CH2Cl2) provided 0.12 g of 37. 1H NMR (400 MHz, d6-DMSO). δ 8.57 (t, J=6 Hz, 1H), 8.47 (s, 1H), 8.23 (bs, 1H), 8.00 (s, 1H), 7.71 (bs, 1H), 7.31 (d, J=8 Hz, 2H), 7.21 (bs, 1H), 6.91 (d, J=8 Hz, 2H), 3.74 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH:15]([NH2:18])([CH3:17])[CH3:16].N1C=CC=CC=1>ClCCl>[CH:15]([NH:18][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3])([CH3:17])[CH3:16]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: CC(C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A suspension of 3 g 5-chlorosulfonyl-2-oxindole, 1.15 g isopropylamine and 1.2 mL of pyridine in 50 mL of dichloromethane was stirred at room temperature for 4 hours during which time a white solid formed. The solid was collected by vacuum filtration, slurry-washed with hot ethanol, cooled, collected by vacuum filtration and dried under vacuum at 40° C. overnight to give 1.5 g (45%) of 5-isopropylaminosulfonyl-2-oxindole.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33]O)[C:22]1[CH:23]=[CH:24][C:25]([Cl:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[Cl:32][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(C(N)=NO)ccc1Cl
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(Cl)c(C(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (461.34 mg; 1.80 mmol) and Intermediate 54 (342.95 mg; 1.50 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 8.68 (d, J=2.1 Hz, 1H), 8.43 (d, J=1.1 Hz, 1H), 8.25 (dd, J=8.3, 2.1 Hz, 1H), 8.17 (dd, J=7.9, 1.7 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.36-7.24 (m, 4H), 7.13 (d, J=7.2 Hz, 1H), 4.28-4.19 (m, 2H), 4 (s, 3H), 3.34 (s, 3H), 2.08 (s, 3H). LC/MS (Method B): 449.1 (M+H)+. HPLC (Method A) Rt 6.10 min (Purity: 96.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[C:9]#[C:10][C:11]2[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[C:9]#[C:10][C:11]2[CH:27]=[CH:26][C:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC(C#Cc2ccc(CNCCC(=O)OC(C)(C)C)cc2)c2cccc(Cl)c2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CC(C#Cc2ccc(CNCCC(=O)O)cc2)c2cccc(Cl)c2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-((4-[3-(3-chlorophenyl)-4-(3,4-dimethylphenyl)but-1-yn-1-yl)benzyl)amino)propanoate in CH2Cl2 (10 mL) was added TFA (1 mL) at room temperature and the mixture was stirred at room temperature for 16 h. The mixture was evaporated under reduced pressure. The residue was diluted with CH2Cl2:MeOH and the mixture was neutralized with NH3:MeOH silica gel was added, concentrated to dryness, then purified by MPLC using MeOH:CH2Cl2 and Compound 3 (129 mg).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH3:12][Si](C=[N+]=[N-])(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][O:2][C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 9.6 g (63.6 mmol) of 4-carboxybenzaldehyde (Aldrich Chemical Co.) in 100 mL of CH2Cl2 at 0° C. was added excess trimethylsilyldiazomethane and the resulting mixture was allowed to stir at 0° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated to give 4.3 g of the ester 167 as an oil. 1H NMR consistent with the product.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[NH2:15])\[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)(Cl)Cl>[F:14][C:11]([F:13])([F:12])[O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:15]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:1][N:2]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: N/C(=N/O)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Yield: 109.5 %

Procedure:
To a solution of (E)-N′-hydroxy-4-(trifluoromethoxy)benzimidamide (3.0 g, 13.6 mmol) and pyridine (1.6 g, 20.4 mmol) in CHCl3 (20 mL), ethyl 2-chloro-2-oxoacetate (2.2 g, 16.4 mmol) was added slowly at 0° C. The mixture was stirred at reflux for 3 h, and then concentrated to give the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=10:1) to give ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate as a white solid (4.5 g, 82%). MS (ES+) C12H9F3N2O4 requires: 302 found: 303[M+H]+.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl[C:47]([O:49][CH2:50][CH:51]([CH3:53])[CH3:52])=[O:48]>CC#N>[CH2:50]([O:49][C:47](=[O:48])[NH:45][C@@H:21]1[CH2:22][C@H:23]([C:25](=[O:44])[N:26]([CH:41]2[CH2:42][CH2:43]2)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[CH2:24][NH:19][CH2:20]1)[CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)COC(=O)Cl
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)OCC(C)C)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and isobutyl chloroformate. MS: 476.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.40 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl.CO>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-1) (3.99 g, 26.0 mmol, 1.0 eq) in dry DCM (150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) is added and the resulting mixture is stirred at RT for 3 h. The reaction mixture is diluted with MeOH (30 mL) and then concentrated in vacuo to yield a slight brown solid. The residue is triturated with H2O (150 mL). The solid is collected by filtration and then re-crystallized in MeOH to afford the product, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (E-2).