Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:39]=[CH:38][C:19]3[N:20]=[CH:21][N:22]([C:23]4[S:24][C:25]([C:35](=[O:37])[NH2:36])=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=5)[N:27]=4)[C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:30]1[CH:29]=[C:28]([C:26]2[N:27]=[C:23]([N:22]3[C:18]4[CH:17]=[C:16]([O:15][CH2:14][CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:39]=[CH:38][C:19]=4[N:20]=[CH:21]3)[S:24][C:25]=2[C:35]([NH2:36])=[O:37])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1sc(-n2cnc3ccc(OCC4CCNCC4)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To 0.13 g (0.23 mmole) of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-yl]-3H-benzoimidazol-5-yloxymethyl}-piperidine-1-carboxylic acid tert-butyl ester (I.23a) in 5 mL of dichloromethane at 0 degrees, was added 5 mL of dichloromethane-trifluoroacetic acid (1:1). The mixture was stirred at 0 degrees for 1 hour and then concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated aqueous sodium carbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from methanol to give 0.10 g of 4-(3-chloro-phenyl)-2-[6-(piperidin-4-ylmethoxy)-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.23). MH+/Z=468
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:25](Cl)[C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(C)[CH3:27].[Mg].C(=O)=O>>[C:13]1([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:25][C:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:4][CH2:3][C:2]([CH3:1])([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:12])[CH3:27]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: CC(C)(C(=O)O)c1ccccc1
Agent: O=C=O
Agent: [Mg]
Product: CC(C)(CCC(C)(C)c1ccccc1)c1ccccc1

Procedure:
A convenient synthesis into 3,3-dimethyl indan-1-one is via the acid catalysed cyclisation of phenylisobutyric acid. The phenylisobutyric acid may be prepared by reaction of neophylchloride with magnesium followed by carbon dioxide under known conditions. Typically, one obtains phenylisobutyric acid in admixture with an unwanted coupling product 2,5-dimethyl-2,5-diphenyl hexane.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CS(=O)(=O)c1ccc(NCC2CC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 40 %

Procedure:
The title compound was prepared according to the procedure described for example 301 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and Cyclopropanemethylamine (40% yield, white foam, MS (m/e): 482.5 (M+H, 100%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([C:21]#[C:22]Br)=[C:6]2[C:10]=1[N:9](S(C1C=CC(C)=CC=1)(=O)=O)[CH:8]=[CH:7]2.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH2:34])[C:29]#[N:30].C1N2CCN(CC2)C1.[OH-].[K+].C(N)CC(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:24])[C:5]([CH2:21][C:22]2[NH:34][C:33]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=3[N:25]=2)=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C#CBr)c(C)cc(Br)c32)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Agent: CC(C)CCN
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Br)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 7-bromo-4-(bromoethynyl)-5-methyl-1-tosyl-1H-indole (35 mg, 0.075 mmol) and 3,4-diaminobenzonitrile (14.96 mg, 0.112 mmol) and DABCO (10.08 mg, 0.090 mmol) in NMP (0.3 mL) was stirred at 100° C. After stirring overnight the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-100% EtOAc in heptanes). The resulting residue was dissolved in EtOH (1.1 mL), KOH (51.8 mg, 0.924 mmol) and isoamylamine (0.21 mL, 1.85 mmol) were added, and the mixture was heated at 100° C. using microwave irradiation for 40 minutes. The resulting residue was purified directly by RP-HPLC (HC-A) to provide the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 11.22 (br. s., 1H) 7.97 (s, 1H) 7.59 (d, J=7.83 Hz, 1H) 7.51 (dd, J=8.21, 1.39 Hz, 1H) 7.33 (t, J=2.91 Hz, 1H) 7.21 (s, 1H) 6.55-6.66 (m, 1H) 4.47 (s, 2H) 2.38 (s, 3H). HRMS calcd. for C18H13BrN4 (M+H)+ 365.0396. found 365.0408.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH:33]1([N:39]=[C:40]=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:40]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:41])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Product: O=C(Nc1ccc(-n2cnc3c(NC(=O)NC4CCCCC4)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and cyclohexyl isocyanate by using the same techniques as in Example 119.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2([C:30](O)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2([C:30]([NH:14][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:16][CH:15]=3)=[O:31])[CH2:29][CH2:28]2)=[O:26])=[CH:22][CH:23]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a 0° C. suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220 mmol) in CH2Cl2 (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 2-4 h until the reaction was complete. CH2Cl2 was removed under reduced pressure. H2O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H2O, the solid was transferred to another flask containing 300 mL of sat. aqueous NaHCO3 solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night on a lyophilizer, affording cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide (4-fluoro-phenyl)-amide (75.8 g, 95% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH:12]([C:17]([O:19]C)=[O:18])[S:13][CH2:14][C:15](=[O:16])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH:12]([C:17]([OH:19])=[O:18])[S:13][CH2:14][C:15](=[O:16])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1Cc2ccc(C3CCCCC3)cc2C(=O)CS1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CSC(C(=O)O)Cc2ccc(C3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
In methanol (150 ml) was suspended methyl 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylate (40 g) followed by addition of 2N-KOH (100 ml), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water, acidified and extracted with etyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and the solvent was distilled off to give 7-cyclohexyl-1,2,4,5-tetrahydro-3-benzothiepin-5-one-2-carboxylic acid (27.5 g, yield 72%). Recrystallization from ethyl acetate gave colorless plates.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Reactant: COc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1ccc(Nc2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 140 °C

Procedure:
A microwave tube was charged with cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.05 g, 0.178 mmol), p-anisidine (0.044 g, 0.356 mmol), bis(dibenzylideneacetone)palladium (0.008 g, 0.009 mmol), xantphos (0.010 g, 0.018 mmol) and sodium tert-butoxide (0.038 g, 0.392 mmol) in dioxane (1 mL). A couple of drops of dimethylacetamide were added to assist with microwave absorption. The mixture was heated at 140° C. for 30 min. The mixture was filtered and concentrated in vacuo. The crude product was purified by preparatory HPLC. LCMS method: 2, RT: 3.49 min, MI: 324 [M+1]. NMR (1H, DMSO, 300 MHz): 10.88 (brs, 1H), 8.73 (s, 1H), 7.43 (4, 1H), 7.33 (d, 2H), 6.99 (d, 2H), 6.95 (d, 1H), 6.24 (d, 1H), 3.11 (s, 3H), 2.08 (brs, 1H), 0.83 (d, 4H)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[CH:13][N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[C:21](OC=O)(=[O:23])C>CN(C)C=O>[CH:21]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[C:8]1=[CH:13][N+:14]([O-:16])=[O:15])=[O:23]
Reactant: O=[N+]([O-])C=C1NCCCN1Cc1ccc(Cl)cc1
Reactant: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCCN(Cc2ccc(Cl)cc2)C1=C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
1-(4-Chlorobenzyl)-2-nitromethylene-hexahydropyrimidine (3 g) was added to a stirred suspension of sodium hydride (0.54 g) in dry dimethylformamide (150 ml) at room temperature under nitrogen and the stirring was continued overnight. Formic acetic anhydride (100% excess) was then added dropwise to the stirred suspension at 0°. The reaction mixture was then stirred for 1 hour. It was then poured onto water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulphate) and the solvent removed in vacuo, to leave a solid. The solid was triturated with chloroform (5 ml) and was then filtered off, washed with chloroform (5 ml) and dried to afford the title compound (1.2 g), m.pt. 131°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1.Cl.N([O-])=O.[Na+].[N-:36]=[N+:37]=[N-].[Na+].C([O-])(=O)C.[Na+]>O>[N:1]([C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]3[CH2:11][CH2:12][N:13]([C:14]([C:16]4[C:17]([CH3:21])=[N:18][O:19][CH:20]=4)=[O:15])[C:7]3([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:6][N:5]2[CH:30]=1)=[N+:36]=[N-:37]
Reactant: COc1ccc(C23Cn4cc(N)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: COc1ccc(C23Cn4cc(N=[N+]=[N-])cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
7-amino-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (190 mg, 0.47 mmol) was mixed with concentrated HCl (0.4 mL) and water (0.4 mL) and the mixture cooled down at 0° C. Aqueous NaNO2 solution (49 mg, 0.70 mmol) in water (0.4 mL) was added dropwise at such rate that the temperature didn't exceed 0-5° C. The mixture was stirred at that temperature for 30 minutes. A solution of sodium azide (44 mg, 0.68 mmol) and sodium acetate (565 mg, 6.9 mmol) in water (2 mL) was then added dropwise at 0-5° C. and the mixture allowed at room temperature and stirred overnight. The mixture was then extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient EtOAc 5 CV, 0%-10% MeOH in EtOAc 9 CV, hold 10% 3 CV and 10-30% 3 CV) to give 7-azido-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (57 mg, yield: 28%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[N:17]2[N:18]=[CH:19][CH:20]=[C:16]2[N:15]=[C:14]([CH3:21])[CH:13]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[N:17]2[N:18]=[CH:19][CH:20]=[C:16]2[N:15]=[C:14]([CH3:21])[CH:13]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1Nc1cc(C)nc2ccnn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n2nccc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of 7-(2-methoxycarbonylphenyl)amino-5-methylpyrazolo[1,5-a]pyrimidine (1.0 g) prepared in Example 3 in ethanol (20 ml) is added a 5% sodium hydroxide solution (30 ml), and the mixture is heated with stirring at 100° C. for one hour. After cooling, the mixture is evaporated to remove ethanol, and the residue is neutralized with a 10% hydrochloric acid, and further the pH value of the mixture is adjusted to pH 4 with a saturated aqueous citric acid solution. The precipitated crystal is collected by filtration, and washed with water, ethanol and ethyl ether, and dried to give 7-(2-carboxyphenyl)amino-5-methylpyrazolo[1,5-a]pyrimidine (970 mg) as colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCn1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)c2ccccc21
Yield: 65.2 %

Procedure:
The same procedures as in Example 140 were carried out from the compound obtained in Example 139 (6.2 g), potassium carbonate (3.6 g), iodomethane (1.6 mL), and DMF (100 mL), to give the captioned compound (4.2 g, 65%) as an oily product.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[NH:9]2)=[CH:4][CH:3]=1.[CH:16](O)=O.C=O.[OH-].[Na+]>O>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CC1(C)CC(=O)N(c2ccc(Br)nc2)N1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1N(c2ccc(Br)nc2)C(=O)CC1(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A suspension of 2-(6-bromo-pyridin-3-yl)-5,5-dimethyl-pyrazolidin-3-one (Example 12, step 1) (800 mg, 2.96 mmol) and formic acid (0.57 ml, 14.8 mmol, 5 equiv.) in water (8 ml) was heated to 100° C. At this temperature formaldehyde (36% in water) (1.13 ml, 14.8 mmol, 5 equiv.) was added drop wise. The mixture was stirred overnight at 100° C. The reaction mixture was cooled and basified carefully with 2N NaOH and extracted two times with a small amount of dichloromethane. The organic layers were loaded directly on a silica gel column and the crude product was purified by flash chromatography eluting with a heptane:ethyl acetate gradient 100:0 to 0:100. The desired 2-(6-bromo-pyridin-3-yl)-1,5,5-trimethyl-pyrazolidin-3-one (380 mg, 45% yield) was obtained as a colorless oil, MS: m/e=284.3/286.3 (M+H+).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][C:35]=1[F:43]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:40](=[O:41])[C:38]2[CH:37]=[CH:36][C:35]([F:43])=[C:34]([C:28]3[C:27]([F:26])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[N:39]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225061) gave 195. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.30 (dd, J=8.7, 4.0 Hz, 1H), 8.15 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.72-7.59 (m, 1H), 7.30 (t, J=8.4 Hz, 2H), 4.86-4.78 (m, 1H), 4.31-4.05 (m, 1H), 4.02-3.83 (m, 2H), 3.75 (s, 3H), 3.11-2.97 (m, 1H), 2.11-2.00 (m, 1H), 1.82-1.50 (m, 5H). LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(OCC)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: CCOc1cccc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.19) (313 g, 1.0 mmol) and commercially available 4-bromobenzenesulfonamide (230 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (190 mg, 41%). MS (ISN) 467.1 [(M−H)−]; mp 245° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=[CH:4][N:3]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>C(O)C>[CH3:21][O:20][C:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]2[N:3]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:1]=2)[CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: COC(=O)Nc1cccc(C)c1COc1cccnc1N
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12

Procedure:
A mixture of 2-amino-3-(2-methoxycarbonylamino-6-methylbenzyloxy)pyridine (4.22 g) and 3-mesyloxy-5-hexyn-2-one (2.74 g) in ethanol (42 ml) was refluxed for 62 hours and then evaporated in vacuo. To the residue was added and aqueous solution of sodium bicarbonate and the insoluble material was collected by filtration. The crude product was purified by column chromatography on silica gel (150 g) with methylene chloride and then a mixture of methylene chloride and acetonitrile (10:1) as eluents to afford a solid, which was recrystallized from a mixture of ethyl acetate and cyclohexane to give 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine.
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH:36]1[CH2:41][CH2:40][SiH:39]([CH2:42][CH2:43][CH3:44])[CH2:38][CH2:37]1>[Cu]I.C1COCC1>[CH2:42]([Si@H:39]1[CH2:40][CH2:41][C@H:36]([CH2:2][CH2:3][C@H:4]2[CH2:9][CH2:8][C@H:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:37][CH2:38]1)[CH2:43][CH3:44]
Reactant: CCC[SiH]1CCC(Br)CC1
Reactant: Clc1ccc(-c2ccc([C@H]3CC[C@H](CCBr)CC3)cc2)cc1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(Cl)cc4)cc3)CC2)CC1

Procedure:
37.8 g (0.1 mol) of 4-(trans-4-(2-bromoethyl)cyclohexyl)-4'-chlorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 22.1 g (0.1 mol) of 1-bromo-4-n-propyl-4-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-propyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-chlorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 10.0 g (yield 22.8%) of the trans isomer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].N1CCC[CH2:10]1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH3:10]
Reactant: COC(=O)CC(C)=O
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(=O)CC(=O)OC
Reaction time: 1 h
Yield: 92.3 %

Procedure:
116 g of acetoacetic acid methyl ester and 75 g of pyrrolidine were boiled in 350 ml of toluene on a water separator until the theoretical quantity of water was separated. The solution was added drop by drop at -40° C. to a suspension of 47 g of sodium amide in 800 ml of liquid ammonia. The ammonia was removed by allowing the temperature of the reaction solution to rise to -20° C., and then, at such temperature, a solution of 114 g of methyl bromide in 500 ml of toluene was added drop by drop. The reaction solution was filtered and the toluene was removed using a rotary evaporator. The residue, after the addition of 700 ml of methylene chloride and 102 g of concentrated hydrochloric acid thereto, was hydrolyzed for 1 hour at ambient temperature. The two phases were separated, the organic phase was dried and the solvent was removed. 120 g of 3-oxopentanoic acid methyl ester (92 percent) was obtained.