Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[N+:12]([C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(O)(=O)C.CCO>[N+:12]([C:15]1[S:19][C:18]([CH:20]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=Cc1ccc([N+](=O)[O-])s1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-nitro-2-thiophenecarboxaldehyde (0.28 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.55 g, in 95% yield, mp: 194.5° C. 1H NMR (DMSO-d6) δ 11.99 (s, 1H), 10.18 (s, 1H), 8.63 (s, 1H), 8.11 (d, 2H), 7.78 (d, 2H), 7.53 (d, 1H), 6.86 (d, 2H). 13C NMR (DMSO-d6) δ 164.9, 162.9, 152.5, 149.0, 142.0, 132.4, 131.8, 131.1, 125.1, 117.0. Anal. Calcd for C12H9N3O4S: C, 49.48; H, 3.11; N, 14.43. Found: C, 49.55; H, 3.09; N, 14.36.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.CI>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)C(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
5-(2-Methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester (13.14 g, 46.3 mmol) was dissolved in tetrahydrofuran (250 mL), 1.09 M lithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (65 mL, 70.9 mmol) was added dropwise at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added methyl iodide (11.7 g, 82.4 mmol) at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate and 0.5N-hydrochloric acid solution, the organic layer was separated, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were combined, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate. The solvent of the filtrate after filtration was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12.36 g, 41.4 mmol, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31].[H-].[Na+].I[CH3:39]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:39])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31]
Reactant: COc1c2n(c3c(NC(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(N(C)C(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-amino)8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.54 g, 1.07 mmol) in anhydrous DMF (6 mL) was treated with sodium hydride (38 mg, 1.60 mmol). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with iodomethane (0.23 g, 1.60 mmol). After stirring at 0° C. for 1 hour, the product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:32][C:33]#[N:34]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:24])[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:32][C:33]#[N:34])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CC(=O)c1cccc(OCc2ccccc2)c1
Reactant: N#CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC#N)C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A stirred solution of 1-(3-benzyloxyphenyl)-2-(2-methylphenyl)ethan-1-one (4 g) in tetrahydrofuran (100 mL) is treated with potassium tert-butoxide (200 mg). After stirring for 30 minutes, it is treated with bromoacetonitrile (0.98 mL), dropwise, and stirring is continued for a further 28 hours. The mixture is then treated with further quantities of potassium tert-butoxide (200 mg) and bromoacetonitrile (0.98 mL) and allowed to stand at room temperature overnight. It is then concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulphate and evaporated, to give a brown oil, which is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:9 v/v), to give 1-(3-benzyloxyphenyl)-3-cyano-2-(2-methylphenyl)propan-1-one, in the form of a colourless oil (0.67 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:26])[S:9]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[CH:25][C:15]=4[C:14]=3[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([C:29]([O-:31])=[O:30])C.O.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:26])[S:9]([C:12]2[CH:21]=[CH:20][C:19]3[NH:18][C:17](=[O:22])[C:16]4[NH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[C:15]=4[C:14]=3[CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)[O-]
Reactant: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1

Procedure:
This compound is prepared according to synthesis 75 from 412 mg (0.93 mmol) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate and 360 mg (13.95 mmol) of lithium hydroxide monohydrate to give, after acid-basic treatment and precipitation in an acid aqueous phase (pH 5), 200 mg (52%) of 8-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a pale pink solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[CH:8]2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[CH:8]2
Reactant: COc1cccc2c1OCC(C(=O)N1CCOCC1)=C2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(C1=Cc2cccc(O)c2OC1)N1CCOCC1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution (70 ml) of 4-(8-methoxy-2H-chromen-3-ylcarbonyl)morpholine (3.5 g) in methylene chloride was added dropwise boron tribromide (9.5 g) at −78° C. The reaction temperature was set to room temperature and the mixture was stirred for 2 hr. The reaction mixture was poured into water and stirred for 1 hr. The organic layer was separated and washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.3 g) as brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in DMF (1 mL) was added methanesulfonyl chloride (51 mg, 0.51 mmol) and DMAP (1 mg). The solution was stirred at rt for 16 h and the product was precipitated with ether, filtered and dried to give 10 mg, 13% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 3.55 (s, 2H), 2.91 (s, 3H).
Reaction SMILES: [O-2:1].[Ca+2:2].C(=O)=[O:4].[C:6]([O-:9])([O-:8])=[O:7].[Ca+2]>O>[OH-:4].[Ca+2:2].[OH-:7].[OH2:1].[C:6]([O-:9])([O-:8])=[O:7].[Ca+2:2]
Reactant: [O-2]
Reactant: O=C=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: [OH-]
Reaction time: 0.25 h

Procedure:
To prepare the aragonitic precipitated calcium carbonate of the invention, a milk of lime (Ca(OH)2) slurry or slake is prepared by adding water to calcium oxide (CaO) with agitation. Preferably, about ten parts water having a temperature of at least about 40° C. (Centigrade) is added to one part CaO to produce a slake having a solids content of about 11 percent, based on the weight of Ca(OH)2 in the solution. The slake is screened to remove grit, typically with a screen that will remove grit of about +60 mesh, and the slake temperature is adjusted to about 50° C. Dry aragonite, such as M60 Aragonite from the Mississippi Lime Company, located in St. Genevieve, Mo., is added, and the slake is agitated for about 15 minutes. Preferably, the amount of aragonite added is equivalent to about five percent of the total amount of precipitated calcium carbonate that will be produced from the slake. Carbon dioxide gas is then added with vigorous agitation. The gas stream rate should be sufficient to convert substantially all of the Ca(OH)2 to CaCO3 in about three hours, forming a precipitated calcium carbonate slurry of about 14 percent solids. Carbonation is complete when the pH falls to 7, at which time the carbon dioxide (CO2) stream is terminated. Typically, between about 9 ft3 and 10 ft3 of CO2 are required for each kilogram of precipitated calcium carbonate produced. The product can then be dewatered to a concentration of about 70 percent solids to produce a cake that can be treated with a typical dispersant, e.g., sodium polyacrylate, and dispersed on a flat-blade or similar dispersion unit.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7][C@@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(=[O:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCCO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 10.2 %

Procedure:
(R)-tert-butyl 3-((R)-(2-acetamidoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (95 mg, 1.88 mmol) was dissolved in 20% v/v TFA/CH2Cl2 (8 mL) at 0° C., the mixture was allowed to warm to rt for 1 h and then concentrated in vacuo to give N-(2-((R)-(3-chloro-2-fluorophenyl)((R)piperidin-3-yl)methoxy)ethyl)acetamide (63 mg, 87%), which was used without further purification. MS (E/Z): 329 (M+)
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Cl)cc1Cl
Yield: 38 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2 mmol) and 2,4-dichloro phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.26 g, 38%). EI-MS m/z 342 (M+H)+
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:31]([CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH2:31][CH2:32][CH3:33])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CCCC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 35.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2-propylpyrrolidine (113 mg, 1.0 mmol). The reaction mixture was then reacted in a microwave at 120° C. for 10 min. Sodium triacetoxyborohydride (220 mg, 1.0 mmol) was then added and the reaction was reacted at room temperature overnight. It was then purified by Gilson Preparatory HPLC to give 21.0 mg of the title compound (38.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1
Reactant: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)cc1
Yield: 21.8 %

Procedure:
To a round bottom flask, a mixture of methyl 3,3-dimethyl-2-(4-(N-methylsulfamoyl) phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (190 mg, 0.49 mmol) in methanol (20 mL), and water (2 mL) was treated with a solution of sodium hydroxide (332 mg, 8.3 mmol) in water (3 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to afford 3,3-dimethyl-2-(4-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (40 mg, yield: 21.9%). MS (ES+APCI) M+1=375.1.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:28])[CH2:26][CH3:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:14][CH2:13][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:4][CH2:3]2)[CH2:26][CH3:27])=[CH:23][CH:24]=1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: CC[C@H](N)c1ccc(Cl)cc1
Product: CC[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Yield: 60 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(4-chloro-phenyl)-propylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 60% of theory; LC (method 5): tR=1.15 min; Mass spectrum (ESI+): m/z=396/398 (Cl) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (245 mg, 1.35 mmol) in THF (2.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (83 mg, 2.02 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-chloro-3-nitrobenzaldehyde (46) (250 mg, 1.35 mmol) in THF was added dropwise. After 2 hours, water was added and the solvent concentrated in vacuo. The solid was filtered and dried to provide the crude title compound. Yield: 190 mg
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9]Br)[C:4]=1[F:11].C[O:13][P:14]([O:17][CH3:18])[O:15][CH3:16]>C1(C)C=CC=CC=1>[CH3:16][O:15][P:14]([CH2:2][C:3]1[C:4]([F:11])=[C:5]([CH2:9][P:14](=[O:13])([O:17][CH3:18])[O:15][CH3:16])[CH:6]=[CH:7][CH:8]=1)(=[O:13])[O:17][CH3:18]
Reactant: COP(OC)OC
Reactant: Fc1c(CBr)cccc1CBr
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cccc(CP(=O)(OC)OC)c1F)OC
Yield: 89 %

Procedure:
A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].Cl>>[NH2:37][C@H:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=5)[CH:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC[C@H](N)C2)nc1
Yield: 86.5 %

Procedure:
Following general procedure A, (S)-tert-butyl 1-(5-(6-(3,5-dichloro-4-hydroxyphenyl)-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (50 g, 0.078 mmol) was treated with a solution of 3N HCl to afford desired product (36.2 mg, 72%) as a yellow-orange solid: 1H NMR (500 MHz, MeOD) δ 9.29 (s, 1H), 8.25 (m, 2H), 8.05 (m, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.31 (m, 3H), 4.52 (s, 1H), 4.06 (d, J=12.6 Hz, 1H), 3.81 (m, 3H); 2.16 (q, J=7.0 Hz, 2H), 2.22 (s, 1H), 1.98 (s, 1H), 1.24 (t, J=7.0 Hz, 3H); APCI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.7% (AUC), tR=10.30 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([N:13](CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][N:13]=[CH:10]2
Reactant: COc1ccc(N)c(C)c1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0° C. then treated with acetic anhydride (2.38 ml), then stirred at ambient temperature for 1 hour, then cooled to 0° C. when a pink solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). This solution was cooled to −5° C., then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water (100 ml). This mixture was stirred vigorously at 0° C. for 10 minutes after which a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13 ml). This solution was heated to 80° C. for 1.5 hours, then cooled and then washed with aqueous 1N sodium carbonate solution. The organic phase was extracted three times with aqueous 2N hydrochloric acid and the acid extracts chilled and then made alkaline by addition of aqueous 5N sodium hydroxide solution. The aqueous layers were extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy-1H-indazole (0.410 g) as a yellow solid. LC-MS (METHOD B): RT=1.32 minutes; 149 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:26]=[CH:25][C:9]2[N:10]=[C:11]([NH:14][CH:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[O:18][CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]([NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=[CH:25][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)COC(NC1CCOc3ccccc31)=N2
Yield: 102.7 %

Procedure:
Prepared from rac-2-chloro-N-[2-(chroman-4-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 120, step A) (186 mg, 0.50 mmol; HPLC 1.092 min) and morpholine (0.87 ml, 10 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (217 mg, 100%; HPLC 0.504 min), MS (ISP) m/e=423.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[C:23]([C:28](O)=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:23]3[C:22]([CH3:21])=[CH:27][CH:26]=[CH:25][N:24]=3)=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cccnc1C(=O)O
Product: Cc1cccnc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-2-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[N:5]=[C:4]([CH3:16])[N:3]=1.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[CH3:16][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[F:15])[CH:7]=[C:2]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:3]=1
Reactant: CC#CCO
Reactant: Cc1nc(Cl)cc(-c2cccc(F)c2F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2cccc(F)c2F)nc(C)n1
Temperature: 25 °C
Reaction time: 11 h
Yield: 86.4 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 401 mg of 4-chloro-2-methyl-6-(2,3-difluorophenyl)pyrimidine and 152 mg of 2-butyn-1-ol, to which 87 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 11 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 395 mg of 2-methyl-4-(2,3-difluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (162)).