Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:30][CH2:29][C:10]3([CH2:13][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=4)=[O:16])[CH2:11]3)[CH2:9]2)=[N:6][CH:7]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:30][CH2:29][C:10]4([CH2:11][CH:12]([NH:14][C:15]([O:17][CH2:18][C:19]5[O:23][N:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=5)=[O:16])[CH2:13]4)[CH2:9]3)=[N:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)C3)C2)on1
Yield: 45.6 %

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.7.). Starting with 0.68 g (1.42 mmol) of ethyl 5-[6-(5-bromopyridin-2-yl)-6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl]isoxazole-3-carboxylate (isomer 6′) and 0.23 g (1.70 mmol) of 4-fluorophenylboronic acid, 1.38 g (4.26 mmol) of caesium carbonate and 0.11 g (0.14 mmol) of PdCl2dppf.CH2Cl2, 0.32 g of a white solid is obtained.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[O:12]=[C:5]1[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=2[C:2](=[O:3])[O:4]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)oc(=O)c2ccccc21
Reaction time: 1 h

Procedure:
Isatoic anhydride (10 g, 1 equiv) in dimethylformamide (30 ml) was added dropwise to a suspension of sodium hydride (2.45 g, 60% in mineral oil, 1 equiv) in dimethylformamide (70 ml) at room temperature. The reaction was stirred for 1 hour prior to the addition of ethyl bromoacetate (6.8 ml, 1 equiv) and the resulting mixture stirred for 16 hours. Solvent evaporated, the residue suspended in water and the solid collected. The title compound was obtained by crystallisation from ethyl acetate (10.5 g). 1H-NMR (CDCl3) δ 1.29 (3H, t), 4.27 (2H, q), 4.82 (2H, s), 6.96 (1H, d), 7.33 (1H, t), 7.74 (1H, dt), 8.19 (1H, dd).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](Cl)(=[O:21])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[S:19](=[O:21])(=[O:20])[NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[C:31]([F:34])([F:32])[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(S(=O)(=O)Cl)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)n(C(=O)OC(C)(C)C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 168 h
Yield: 20.7 %

Procedure:
This compound was prepared in analogy to Example 1 starting from 2-chlorosulfonyl-5-fluoro-3-methyl-indole-1-carboxylic acid tert-butyl ester (0.29 g) and 2-amino-5-bromobenzotrifluoride (2.0 g) in pyridine (5 ml) by stirring for 7 days at rt to obtain the title compound (0.095 g) as a colorless foam. MS (ISN): 551.4, 549.3 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>O1CCCC1>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[N:10][N:11]=1)[OH:24]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(Cn2cnnn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnnc2C(O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
A solution of 1-(4-methoxybenzyl)tetrazole (6.12 g; Y. Satoh and N. Marcopulos, Tetrahedron Letters, 1995, 36, 1759-1762), and N,N,N'N'-tetramethylethylenediamine (10 ml) in dry tetrahydrofuran (10 ml) under nitrogen was cooled to -95° C. and treated dropwise with n-butyl lithium (2.5 M solution in hexanes) over 15 minutes. The reaction mixture was left at -80° C. for 15 minutes when 2-chlorobenzaldehyde (4.53 g) was added dropwise over 10 minutes maintaining the reaction temperature at or below -80° C. The mixture was stirred at or below -80° C. for 30 minutes, allowed to warm to room temperature, quenched with ammonium chloride solution (50 ml) and the organic phase separated. The aqueous phase was extracted three times with ethyl acetate (50 ml), the combined organics dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:1, v/v) then with a mixture of ethyl acetate and pentane (2:1, v/v). Fractions homogenous in the required product were combined and evaporated affording the title compound (1.33 g) as a white solid, m.p. 128-130° C. [Elemental analysis:-C,58.22; H,4.74; N,17.15%. Calculated:-C,58.1; H,4.57; N,16.94%].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:25]=1[CH3:26].C(N(CC)CC)C.[Al]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1ccccc1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4ccccc4)c3C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (30.0 mg, 0.119 mmol), 4-iodo-5-methyl-1-phenyl-1H-pyrazole (33.8 mg, 0.119 mmol), tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.012 mmol) and copper (I) iodide (6.79 mg, 0.036 mmol) were suspended in DMF (1 mL) and triethylamine (0.033 mL, 0.238 mmol) was added. The flask was wrapped with aluminum foil and sparged with nitrogen for 5 minutes. The reaction was stirred at ambient temperature for 1 hour, then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate two times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure to give 4-methoxy-3-[(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethynyl]-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:4]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 80 %

Procedure:
The mixture of 4-piperidone hydrochloride (0.851 mol), triethylamine (1.70 mol), 4-fluoronitrobenzene (0.851 mol) in 800 ml chloroform was heated under reflux for 16 hours. The solvent was removed under vacuum and to the residue water (1 liter) was added and the precipitate was filtered to afford 4-[4-oxo-piperidin-1-yl]-nitrobenzene in 80% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([O:10]CC=C)=[O:9])[CH:2]=[CH2:3].[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>CO.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(OCC=C)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cccc(C(=O)O)c1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 917 mg (4.2 mmol) of 3-(2-propenyloxy)benzoic acid, 2-propenyl ester in 9 mL of methanol/water (3:2) at room temperature is treated with 0.53 mL (5.25 mmol) of 10M sodium hydroxide solution. The solution is allowed to stir for one hour then acidified with 5 mL of 10% sodium bisulfate solution and extracted with 25 mL of ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 732 mg (97%) of 3-(2-propenyloxy)benzoic acid as a white powder. The product is utilized in the next reaction without further purification; m.p. 78°-79°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3000, 1690, 1620, 1590 cm-1 ; MS (CI low res) m/e 179 (M+H), 161, 135; Analysis calculated for C10H10O3 : C, 67.41; H, 5.66; found: C, 67.37; H, 5.59.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[O:28][C:27](=O)[C:26]2[S:30][CH:31]=[CH:32][C:25]1=2)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[O:28][C:27](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[C:26]2[S:30][CH:31]=[CH:32][C:25]1=2)[CH3:23]
Reactant: CCC1OC(=O)c2sccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2sccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (91 mg, 0.6 mmol.) in THF (1 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1 M solution in THF, 1.2 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 4-ethyl-4H-thieno[2,3-c]furan-6-one, (67 mg, 0.4 mmol) in THF (1.5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (50 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried to give the title compound as a yellow solid (68mg, 57%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([P:9]([O-:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]>>[CH2:7]([P:9]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: C=C1CC(=O)O1
Reactant: CCCCOP([O-])CC
Product: CCCCOP(=O)(CC)CC1CC(=O)O1
Temperature: 85 °C

Procedure:
A solution of 0.98 parts of bis-(t-butylcyclohexyl)perdicarbonate in 12.6 parts of diketene was added dropwise over 1 hour to 90.2 parts of n-butyl ethylphosphonite which was vigorously stirred at 85° C. in a nitrogen atmosphere. After the addition the reaction mixture was passed down a wiped wall still at a temperature of 50° C. and a pressure of 0.13 mb to remove the excess phosphonite. The residue was distilled on the wiped wall still at a temperature of 75° C. and a pressure of 0.013 mb. The product n-butyl ethyl(2-oxo-4-oxetanylmethyl)phosphinate, was obtained as a colourless oil which the 31P NMR showed to be a nearly equal mixture of diastereoisomers having chemical shifts of δ-52.4 and δ-52.7 and which had the following elemental analysis by weight.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH2:33]([N:35]([CH2:40][CH3:41])[CH2:36][CH2:37][CH2:38][NH2:39])[CH3:34]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:32])[NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:40][CH3:41])[CH2:33][CH3:34])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: CCN(CC)CCCN
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: CCN(CC)CCCNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 85 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N,N-diethyl-1,3-propanediamine (available from Aldrich Chemical Company, Inc.; 81 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-diethylamino-propylcarbamoyl)-biphenyl-2-carboxylic acid (104 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.63 (br s, 1H), 9.48 (br s, 1H), 1H NMR (400 MHz, DMF), d ppm 9.14 (t, J=5.6 Hz, 1H), 8.92 (s, 1H), 8.83 (d, J=1.8 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.68 (dd, J=8.0, 2.0 Hz, 1H), 8.52 (dd, J=8.3, 2.0 Hz, 1H), 8.34 (d, J=8.3 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 3.77-3.84 (m, 2H), 3.51-3.63 (m, 6H), 2.28-2.38 (m, 2H), 1.62 (t, J=7.2 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[C:5]([F:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:13])[C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: O=C1COc2c(F)ccc(F)c2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2c(F)ccc(F)c2N1CCCCl
Yield: 16.8 %

Procedure:
5,8-Difluoro-4H-benzo[1,4]oxazin-3-one (1.86 g, 10 mmol), Cs2CO3 (4.91 g, 15 mmol), and 1-chloro-3-iodopropane (2.04 g, 10 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 17%). Rf=0.74 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) d 6.86-6.73 (m, 2H), 4.60 (s, 2H), 4.18-4.12 (m, 2H), 3.56 (t, J=6.4 Hz, 2H), 2.20-2.12 (m, 2H); 13C NMR (CDCl3) d 164.7, 148.4 (dd, J=243.9 Hz, J=2.8 Hz), 147.5 (dd, J=243.7 Hz, J=3.0 Hz), 136.6 (dd, J=16.2 Hz, J=5.0 Hz), 119.8 (dd, J=11.2 Hz, J=2.7 Hz), 111.5 (dd, J=20.4 Hz, J=9.6 Hz), 110.4 (dd, J=24.8 Hz, J=7.9 Hz), 68.6, 42.4 (d, J=10.0 Hz), 42.1, 31.1 (d, J=3.5 Hz).
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][N:12]=2)/[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[NH2:45]>C1COCC1.CN(C=O)C>[CH:1]1(/[CH:6]=[C:7](\[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][N:12]=2)/[C:8]([NH:45][C:41]2[S:40][CH:44]=[CH:43][N:42]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)O)nc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)nc1

Procedure:
A solution of (E)-3-cyclopentyl-2-(5-methylsulfanylpyridin-2-yl)acrylic acid (Preparation 5, 1.00 g, 3.8 mmol), EDCI (0.95 g, 4.9 mmol), HOBt (0.67 g, 4.9 mmol) and thiazol-2-ylamine (1.52 g, 15.2 mmol) in anhydrous THF (62 mL) and DMF (50 mL) was stirred at 20° C. for 4 d. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 and saturated aqueous Na2CO3. The organic layer was washed with H2O and brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (7:31H-EtOAc) provided the title compound: RTA=3.96 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1.[F:35][C:36]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:35][C:36]1([F:42])[CH2:41][CH2:40][N:39]([C:2]2[CH:34]=[CH:33][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[C:13]([O:16][CH2:17][C:18]5[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=5)[CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]3[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=2)[CH2:38][CH2:37]1
Reactant: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Reactant: FC1(F)CCNCC1
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(N5CCC(F)(F)CC5)cc4)c3c2)n1

Procedure:
The title compound was prepared from racemic cis-2-(1-(4-bromobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid using analogous conditions to Example 152 using 4,4-difluoropiperidine. MS (ESI): mass calcd. for C31H35F2N5O3, 563.65; m/z found, 564.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.55-7.48 (m, 2H), 7.04 (d, J=8.7, 2H), 6.96 (dd, J=10.0, 5.5, 3H), 6.93-6.88 (m, 1H), 6.27 (d, J=2.2, 1H), 5.43 (d, J=16.7, 1H), 5.38 (d, J=16.7, 1H), 4.99 (s, 2H), 3.83 (s, 3H), 3.61-3.52 (m, 1H), 3.34-3.32 (m, 4H), 2.88-2.79 (m, 1H), 2.43-2.29 (m, 1H), 2.12-1.93 (m, 5H), 1.93-1.66 (m, 4H), 1.57-1.37 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[S:37])=[O:34])=[CH:28][CH:27]=1>C(#N)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:35][C:36](=[S:37])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:2]3[C:7]4=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]4[N:5]=[CH:4][N:3]=3)=[CH:41][CH:40]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)cc1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCOC(=O)c1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (7.2 mg, 0.03 mmol) (for preparation see U.S. Pat. No. 6,670,357, the disclosure of which is herein incorporated by reference) and DABCO (7 mg, 0.06 mmol) in acetonitrile (0.5 mL) was added 1-(2-(4-fluorophenyl)acetyl)-3-(4-hydroxyphenyl)thiourea (0.5 mL, 0.05 mmol). The reaction was shaken at room temperature. After 30 min, LC/MS analysis indicated mostly product. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness. Purification by silica gel chromatography (eluting with 1% methanol/dichloromethane) provided the desired product contaminated with impurities. A second purification by silica gel chromatography (1–6% Ethyl acetate/dichloromethane) again did not remove all of the impurities. The resulting solid mixture was washed with methanol and dried to provide the title compound (6 mg, 39%) as a yellow solid. 1H NMR (CDCl3) δ 12.32 (s, 1H), 8.62 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.76 (m, 2H), 7.29 (m, 4H), 7.12 (m, 2H), 4.38 (q, 2H, J=7.1 Hz), 3.72 (s, 2H), 2.82 (s, 3H), 1.40 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 508 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH:12]([CH3:16])[CH2:13][CH:14]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH2:26].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:25][NH:26][CH2:14][CH2:13][CH:12]([CH3:16])[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: CC(CC=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the aldehyde from Step (a) (0.55 g, 1.47 mmol) and methylamine (2M solution in THF, 1.48 ml, 2.95 mmol) in dry dichloromethane (5 ml) was added acetic acid (0.5 ml) followed by sodium triacetoxyborohydride (0.63 g, 2.95 mmol). The mixture was stirred at room temperature for 16 hours before quenching with saturated aqueous sodium bicarbonate solution (10 ml) and separating the phases. The organic phase was dried (MgSO4) and evaporated under reduced pressure to yield as a mixture of diastereoisomers (3RS, 4RS)-N-methyl-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methyl-butyl]amine as a gummy yellow solid, which was carried on to the next stage without further purification.
Reaction SMILES: I[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C[Sn](C)(C)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O1CCOCC1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1-c1ccccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In a 25 mL pear shaped flask was placed 5-iodo-2'-deoxycytidine (0.425 g, 1.2 mmol), 2-trimethylstannylpyridine (1.4 g, 5.8 mmol), Bis (triphenylphosphine)-palladium (II) chloride (0.084 g, 0.12 mmol), and anhydrous 1,4-dioxane (15 mL). The reaction was heated at 60° C. for 15 hrs then at 90° C. for 1 h. The solvent was evaporated and the residue purified by silica gel chromatography (10% CH3OH in CH2Cl2 (1% NH3)) to yield 0.173 g (47%) of the title compound as a white solid m.p. 197°-198° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:7][CH:13]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1coc(-c2cccs2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of 2-thiophenecarboxamide (5.09 g) and 1,3-dichloroacetone (457 g) was stirred at 120° C. for 2 hours. The reaction mixture was poured into water, nautralized with potassium carbonate, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane (1:9, v/v), 4-chloromethyl-2-(2-thienyl)oxazole (4.09 g, 57%) was obtained. Recrystallization from isopropylether gave colorless needles, mp 59-59° C.