Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=O)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(O)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:16][C:15](=[O:17])[N:14]([CH3:18])[C:13](=[S:21])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)[nH]2)cc1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2cc(=S)n(C)c(=O)[nH]2)cc1OC
Yield: 106.9 %

Procedure:
To a suspension of 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.5 g) in dioxane (15 ml) was added phosphorus pentasulfide (1.27 g) and the mixture was refluxed for 2 hours. After being cooled, ethanol (15 ml) was added thereto, and the mixture was refluxed for 2 hours again. After being cooled, the resulting precipitates were collected by filtration and washed successively with ethanol and diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-pyrimidinone (0.85 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[Br:11]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([Br:11])=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1csc(N)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
2-Amino-4-[(1,1-dimethyl)ethyl]thiazole (0.87 g, 5.6 mmol) was dissolved in carbon tetrachloride (9 mL). N-Bromosuccinimide (1.00 g, 5.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture, the insoluble matter was filtered off, and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) to give the title compound (1.23 g, 93.7%) as a yellowish gray powder.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24]>C(O)C.[Pd]>[CH2:27]([O:26][C:22]([CH2:23][CH2:24][N:8]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9]1)=[O:25])[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C(=O)OCC)C1
Temperature: 70 °C
Yield: 57.9 %

Procedure:
A solution of (±) ethyl N-benzyl-3-pyrrolidinyl carboxylate (D1) (100 g, 0.43 mole) in ethanol (800 ml) was treated with ammonium formate (135.32 g, 2.15 mole) and 10% Pd on carbon (25 g) then heated at 70° C. for 2h. After 1h a further addition of 10% Pd on carbon (10 g) was made. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in ethanol (500 ml), treated with ethyl acrylate (51.56 g, 0.52 mole) then heated under reflux for 1h. The reaction mixture was concentrated in vacuo, treated with saturated aqueous potassium carbonate, then extracted into chloroform. The combined organic extracts were dried (Na2SO4), concentrated in vacuo and the residue distilled to afford the title compound (D2) as an oil (60.53 g, 58%), b.p. 135°-145° C. at 4 mmHg.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.[H-].[Na+].[CH3:16][O:17][CH2:18]Cl>O>[CH3:16][O:17][CH2:18][O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Br)cc1
Temperature: 30 °C
Yield: 79.1 %

Procedure:
Into a reactor, 40 g of p-bromophenol and 200 ml of DMF (dimethylformamide) were charged, to which 10 g of a 60% NaH (sodium hydride) were gradually added to give a solution. To the solution, 18 g of methoxymethyl chloride were added dropwise with stirring at a temperature of 30° C. or lower, and reacted overnight at room temperature to give a reaction solution. The reaction solution was poured into water, extracted with benzene, washed with water, dried over sodium sulfate anhydride, and thereafter the solvent was evaporated and the residue was distilled under reduced pressure to give 38.4 g (Y., 79.3%) of 4-bromopheny methoxymethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[CH:10]2[CH3:13])=[CH:5][CH:4]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:14])[C:10]2([CH3:13])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C)C(=O)CC2
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC1(C)C(=O)CCc2ccc(OC)cc21

Procedure:
The compound 3,4-dihydro-7-methoxy-1-methyl-2(1H)-naphthalenone (VIIIb) (28.23 g, 148 mmol) was reacted with ethyl bromoacetate by the method of Example 5 to yield 36.0 g (88%) (IXb) b.p. 138°-140°/0.1 mm Hg; IR (neat) 1740 cm-1 (unresolved ketone and ester bands); NMR δ, 1.05 and 3.93 (triplet and quartet for CO2CH2CH3), 1.37 (s, 3, CH3), 3.80 (s, 3, OCH3), 6.6-7.3 (m, 3, ArH). The distillate crystallized on standing. A sample recrystallized from ethanol melted at 55°-55.55°.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[N-:11]=[N+:12]=[N-:13].[Na+].CN(C)C=O>C(OCC)C>[CH:1]([CH:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CC(N=[N+]=[N-])c1ccccc1
Yield: 100.7 %

Procedure:
A mixture of 100 grams (655 mmol.) of vinylbenzyl chloride (mixture of m- and p-isomers), 42.6 grams (655 mmol.) of sodium azide and 500 mi. of dimethylformamide was stirred at room temperature for 24 hours. Ethyl ether, 500 mi., was then added and the mixture was extracted with two 300-mi. portions of water. The combined aqueous phases were extracted with 500 mi. of ethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to yield 105 grams (100% of theoretical) of vinylbenzyl azide. The structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:16][C:17]=2F)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([N:20]3[C:28]4[CH2:27][C:26]([CH3:30])([CH3:29])[CH2:25][C:24](=[O:31])[C:23]=4[C:22]([CH3:32])=[CH:21]3)=[CH:16][C:17]=2[S:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:12]=[CH:11][N:10]=1
Reactant: Cc1cn(-c2cc(F)c3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Reactant: CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1cc(-n2cc(C)c3c2CC(C)(C)CC3=O)cc2ncnc(N)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a small microwave vial with a stir bar, butanethiol (0.494 mmol, 44.56 mg) is dissolved in 3 mL DMF. To this solution is added NaH (60% suspension in mineral oil) (0.494 mmol, 20 mg) and the mixture is stirred at rt for 5 minutes and then 1-(4-Amino-5-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.0988 mmol, 33.4 mg) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 120° C. for 30 min. The reaction is cooled and quenched by pouring into 30 ml sat. NH4Cl aq. and extracted 3 times with 10 mL EtOAc. The combined organics are dried with Na2SO4, concentrated, and purified by silica gel chromatography on Biotage using a gradient of 0-20% MeOH in DCM. 1-(4-Amino-5-butylsulfanyl-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one is isolated (22.1 mg, LC/MS m/z=409 [M+H]+) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][C@@H:37]([CH3:40])[CH2:38][OH:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol using methods similar to Example 563 to provide a tan solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.74 Hz, 3 H), 1.65-1.80 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.21 (t, J=5.16 Hz, 2 H), 3.37 (t, J=7.79 Hz, 2 H), 3.48 (t, J=5.16 Hz, 2 H), 4.00-4.12 (m, 1 H), 4.16-4.28 (m, 4 H), 5.00 (t, J=5.16 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.41 (dd, J=8.74, 5.58 Hz, 2 H), 7.99 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.37 (d, J=8.63 Hz, 1 H), 17.26 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13]CC)=O.[CH2:16]([NH:23][C:24](=O)[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH2:16]([N:23]1[C:11](=[O:13])[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]=2[N:1]=[C:24]1[C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(-c2nc3sc4c(c3c(=O)n2Cc2ccccc2)CCCC4)cc(OC)c1OC
Temperature: 0 °C
Yield: 68 %

Procedure:
Commercially available ethyl 2-amino-4,5,6,7-tetrahydrobenzo(b)-thiophene-3-carboxylate (6.0 g, 26.6 mmol, 100 mol-%) and N-benzyl-3,4,5-trimethoxybenzamide (10.4 g, 34.6 mmol, 130 mol-%) were dissolved in dry 1,2-dichloroethane. The reaction mixture was cooled with an ice-salt-bath and POCl3 (1.7 ml, 24.6 mmol, 130 mol-%) was added. The reaction mixture was refluxed for 24 hours. During refluxing POCl3 (340 μl) was added twice. The reaction mixture was poured into ice-water and after neutralization with sodium acetate the product was extracted into dichloromethane. The organic phases combined were washed with sodium bicarbonate sat. (3×50 ml) and dried with MgSO4. The yield after recrystallization from i-propanol was 8.3 g (yield 68%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>CC(C)=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 81.4 %

Procedure:
A mixture of 4-cyanophenol (11.91 g, 100.0 mmol), K2CO3 (55.20 g, 400.0 mmol), and 4-fluorobenzylbromide (22.68 g, 120.0 mmol) were heated in acetone (400 mL) at reflux (5 h). The volatiles were evaporated and the residue was diluted in CH2Cl2 (300 mL), and then washed with H2O (500 mL), dried (MgSO4), and concentrated in vacuo. The solid was recrystallized with MeOH to give white needles (18.50 g, 81%): Rf=0.89 (hexanes/EtOAc 911); mp 82-83° C.; 1H NMR (CDCl3) δ 5.07 (s, CH2O), 7.01 (d, J=9.0 Hz, 2 ArH), 7.09 (t, J=8.7 Hz, 2 ArH), 7.37-7.42 (m, 2 ArH), 7.59 (d, J=9.0 Hz, 2 ArH); 13C NMR (CDCl3) δ 69.5 (CH2O), 104.2 (CCN), 115.5 (ArC), 115.6 (d, J=22.5 Hz, C3′), 119.0 (CN), 129.4 (d, J=7.9 Hz, C2′), 131.4 (C1′), 133.9 (ArC), 161.7 (ArC), 162.6 (d, J=245.6 Hz, C4′); Anal. Calcd. for C14H10FNO2: C, 74.00; H, 4.44; F, 8.36; N, 6.16. Found: C, 74.06; H, 4.28; F, 8.26; N, 6.16.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][S:36]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([F:27])[CH:29]=2)(=[O:37])=[O:38])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)c2ccc(OC)c(F)c2)c1-c1cccc(N)c1
Yield: 76.1 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (100 mg; 0.28 mmol) and 3-fluoro-4-methoxy-benzenesulphonyl chloride (115 mg; 0.51 mmol), 115 mg of the title compound are obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73][NH2:74])=[CH:69][CH:68]=1>CN(C=O)C>[CH3:65][O:66][C:67]1[CH:72]=[CH:71][C:70]([CH2:73][NH:74][C:1]([C:4]2[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])=[CH:69][CH:68]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1ccc(CN)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2cccc(B(O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3-Carboxyphenylboronic acid (140 mg, 0.84 mmol), PyBOP (376 mg, 0.72 mmol) and HOBt (97.7 mg, 0.72 mmol) were dissolved in DMF (3.18 mL) and treated with DIPEA (420 μL, 2.41 mmol). After 5 min at ambient temperature, 4-methoxybenzenemethanamine (78 μL, 0.60 mmol) was added. The homogeneous reaction mixture was stirred at ambient temperature for 16 h, the solvent was removed under reduced pressure, and the residue purified by preparative HPLC (5-40% MeCN over 40 min, 35 mL/min) to afford the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:11][C@:10]([CH3:16])([C:12]([F:15])([F:14])[F:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Br)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:11]2[C:4]3=[N:3][C:2]([Cl:1])=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][C@@:10]2([CH3:16])[C:12]([F:13])([F:14])[F:15])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(Cl)cc2=O)N1CCc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 40 mL of DMF, 2 g (7.89 mmol) of (S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 3.44 g (11.84 mmol) of 1-benzyloxy-4-(2-bromoethyl)benzene and 5.14 g (15.78 mmol) of cesium carbonate is heated in a Biotage microwave reactor at 120° C. for 20 minutes. The reaction medium is evaporated to dryness. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 20% B, t 25 min 50% B, t 35 min 50% B), 2.8 g of (S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained, corresponding to the following characteristics:
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:19])=O)[CH:12]=3)=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[N:24]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:2]1([C:5]2[N:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:29][C:25]4[N:24]=[C:23]([C:22]([O:21][CH3:20])=[O:30])[CH:28]=[CH:27][CH:26]=4)=[O:19])[CH:12]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc(N)n1
Reactant: O=C(O)c1cc(-c2ccc(C3CC3)nc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(-c3ccc(C4CC4)nc3)ccn2)n1

Procedure:
A solution of 6-cyclopropyl-3,4′-bipyridine-2′-carboxylic acid hydrochloride salt (1.73 g, 6.25 mmol), 6-aminopicolinate methyl ester (1.05 g, 6.87 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 2.85 g, 7.50 mmol), and N-methylmorpholine (1.51 mL, 13.8 mmol) in N,N-dimethylformamide was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 mL) and dried under reduced pressure to afford methyl 6-(6-cyclopropyl-3,4′-bipyridine-2′-carboxamido)picolinate as a white powder, which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 46.1 %

Procedure:
An 8 mL vial was charged with compound 5 (20 mg, 0.0446 mmol), Lawesson's reagent (19.9 mg, 0.0491 mmol). Toluene (3 mL) was added, and the vial was sealed and placed into CEM microwave reactor and irradiated at 130° C. for 1 h. After cooling down, the solvent was removed by evaporation in vacuo and the resulting residue was purified by preparative TLC (hexane: EtOAc=2:1) to give compound 6 (10 mg, 47%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>[Pd]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(Cl)=C(C=O)C1
Agent: [Pd]
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 2-chloro-5,5-dimethylcyclohex-1-enecarbaldehyde, 4-chlorophenylboronic acid, a first phase transfer catalyst, a fifth base, and a first palladium catalyst to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:19][CH2:18]1.C1(C)C(C)=CC=CC=1>O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:6](=[O:8])[CH:3]3[CH2:2][CH:1]([CH2:5][CH2:4]3)[C:9]2=[O:11])[CH2:22][CH2:21]1
Reactant: NCCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: O=C(O)C1CCC(C(=O)O)C1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic acid (1.6 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-quinolyl)piperazine (2.8 g., 10 mmole) were combined in 200 ml. of xylene and refluxed for 24 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuum and the residue redissolved in chloroform and filtered through 75 g. of silica gel. The column was rinsed with 5% ethanol/chloroform and the product-containing fractions were combined and evaporated. The residue was recrystallized from isopropanol with the addition of 4N isopropanolic HCl to give 820 mg. of the title compound as the dihydrochloride hemihydrate; m.p. 240°-242° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:29](O)=[O:30])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:21][CH2:20][C:19]4[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=4[NH:17][C:16]3=[O:28])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:32]1([C:29]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([N:9]3[CH2:14][CH2:13][CH:12]([N:15]4[CH2:21][CH2:20][C:19]5[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=5[NH:17][C:16]4=[O:28])[CH2:11][CH2:10]3)[CH:5]=2)=[O:30])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)c(C#N)cn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ccccc54)c(C#N)cn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.02 g (0.48 mmol) 5′-cyano-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid, 57 mg (0.48 mmol) 2,3-dihydro-1H-indole and 0.21 mL (1.5 mmol) TEA were placed in 3 mL DMF. 0.17 g (0.52 mmol) TBTU were added. The reaction mixture was stirred overnight at RT and then purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: N#Cc1ccccc1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 130 °C
Yield: 36 %

Procedure:
A mixture of 2-amino-5-bromopyridine (2.00 g, 11.6 mmol), copper (I) bromide (160 mg, 1.09 mmol), 1,10-phenanthroline monohydrate (225 mg, 1.12 mmol) and benzonitrile (25 mL) was heated in a 50-mL 3-necked flask to 130° C. During 24 h a gentle flow of (O2/N2 5:95) was bubbled through the reaction mixture (>97% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 6-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.14 g, 36%) as a light brown solid with 99.7% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: Br[C@H:2]([C@H:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1CCN2C(=NCCC2)CC1>CCOCC>[O:14]1[C@H:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C@H:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)[C@@H](O)[C@@H](Br)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
2a (38.1 g, 142 mmol) was dissolved in anhydrous Et2O (100 ml) and DBU (32.3 g, 212.4 mmol, in Et2O [50 ml]) was added dropwise at 0° C. for 1 h. The reaction was allowed to warm to r.t. and stirred for an additional 4 h. Reaction was quenched with cold 1N HCl to pH˜5. The resulting aqueous layer was extracted with Et2O (3×150 ml). The combined organic extracts were washed with brine (2×100 ml), dried over Na2SO4, and concentrated to give the pure product as faintly yellow oil (21.5 g, 80.7% yield). Product purity typically reflects that of the bromohydrin starting material. If necessary, fractional vacuum distillation can be used for purification. 1H NMR (CDCl3, 400 MHz): δ 4.36-4.22 (m, 4H); 3.67 (s, 2H); 1.35-1.31 (t, 6H). 13C NMR (CDCl3, 100 MHz): 166.75, 62.21, 52.01, 14.01.