Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][CH2:8]P(=O)(OCC)OCC)[CH:6]=[CH:5]C=C[CH:2]=1.C([Li])CCC.CN1CCN([C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[C:33](=[O:40])[C:32]3[CH:41]=[CH:42][CH:43]=[CH:44][C:31]=3[CH:30]=2)CC1.Cl>C1COCC1.C(Cl)(Cl)Cl>[S:7]1[CH:8]=[CH:5][CH:6]=[C:1]1/[CH:2]=[C:29]1\[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=[O:40])[CH2:32][C:41]2[CH:42]=[CH:43][CH:44]=[CH:31][C:30]\1=2
Reactant: CCOP(=O)(CSc1ccccc1)OCC
Reactant: CN1CCN(c2cc3ccccc3c(=O)c3ccccc23)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2/C(=C/c2cccs2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 175.3 %

Procedure:
To a stirred solution of 3.25 g (12.5 mmol) of diethyl phenylthiomethylphosphonate in 7.0 mL of THF at 0° C. under N2 was added 7.8 mL of a 1.6M solution of n-butyllithium dropwise via syringe. The solution was stirred at 0° C. for 45 minutes, followed by the dropwise addition of a solution of 3.04 g (10.0 mmol) of 10-(4'-methylpiperazin-1-yl)-5H-dibenzo[a,d]cyclohepten-5-one in 10.0 mL of THF via cannula. After stirring for 1 hour at 0° C., the solution was warmed to 22° C. over 45 minutes, and stored at -5° C. for 48 hours. The reaction mixture was poured into 200 mL of 5% HCl and stirred rapidly with 300 mL of CHCl3 for 1 hour. The organic layer was worked up to give 5.3 g of a yellow foam which was chromatographed on 500 g of SiO2 using CHCl3 to give 2.14 g (65%) of product as a yellow foam. A small sample was crystallized from CH3OH to give a pale yellow solid. m.p. 203.5°-205° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.CCOC(C)=O.[Cl:25][C:26]1[CH:31]=[C:30](CCl)[CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:17])[NH:15][CH3:16])[CH2:12][CH2:13]2)[CH:29]=[CH:28][N:27]=1
Reactant: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)N1CCN(Cc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
1-Boc-4-(N-methylcarbamoyl)piperazine was treated with 8 M HCl/EtOAc to afford a salt, then the salt (1.0 equiv) was mixed with 2-chloro-4-(chloromethyl)pyridine (1.0 equiv) (Preparation B-11) and K2CO3 (4 equiv) in DMF. The mixture was stirred for 1 h at rt. After removing most of the solvent, the residue was partitioned in water and EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography to give the title compound as a solid (˜90% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[C:26](Cl)=[N:27][C:28]([Cl:31])=[N:29][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH:10][C:26]1[C:25]([Cl:24])=[CH:30][N:29]=[C:28]([Cl:31])[N:27]=1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)c(C)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)c(C)c1Nc1nc(Cl)ncc1Cl
Yield: 2 %

Procedure:
A solution of 3-amino-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.25 g, 5.06 mmol), potassium carbonate (0.7 g, 5.06 mmol) and trichloropyrimidine (2.78 g, 15.2 mmol) was heated at 50° C. in DMF (10 mL) for 16 hours. The mixture was diluted with ethyl acetate, washed with brine and water, and dried over sodium sulfate. Evaporation of solvent and column chromatography (hexane and ethyl acetate (9:1)) gave 39 mg of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester in 2% yield: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 7.5 (m, 5H), 3.82 (s, 3H), 2.37 (s, 3H); MS (m/e): 393.9 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1)=O.[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO.C(O)C>[N:20]1([CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:1][C:3]3[CH:8]=[CH:7][C:6]([O:9][S:10]([C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)(=[O:12])=[O:11])=[CH:5][CH:4]=3)=[CH:32][CH:33]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Oc2ccc(CNc3ccc(OCCN4CCCC4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A solution of toluene-4-sulfonic acid 4-formyl-phenyl ester (3.28 g, 11.88 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (2.45 g, 11.88 mol) in 40 mL of methanol was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. A portion of the crude residue (1.36 g, ˜2.92 mmol) was dissolved in 35 mL of ethanol and was treated with sodium borohydride (0.687 g, 18.16 mmol), which was added in portions over a period of about 3 hr. The reaction was stirred at room temperature overnight at which time it was concentrated to one-half of its original volume. To this mixture was added 25 mL of water and 25 mL of saturated sodium bicarbonate. The mixture was extracted three times with methylene chloride and the combined organic layers were dried (magnesium sulfate), filtered, and concentrated. Medium pressure silica gel chromatography of the residue (2% methanol/methylene chloride to 10% methanol/methylene chloride) afforded 1.06 g (80%) of the title compound. MS 467.1 (M+1)+
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:4]=1[CH2:5][C:6]1[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=12.S(OC)(O[CH3:23])(=O)=O.O>CS(C)=O>[CH3:23][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:6]2[CH2:5][C:4]3[C:15]([C:7]1=2)=[CH:16][CH:17]=[CH:18][CH:3]=3
Reactant: c1ccc2c(c1)Cc1c-2[nH]c2ccccc12
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c2c(c3ccccc31)Cc1ccccc1-2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (375 mq, 15.6 mmol) was added to dimethylsulfoxide (DMSO) (13 cm3) under an atmosphere of nitrogen. The solution was then heated to 70° C. until no more gas (H2) evolved. The solution was cooled to room temperature and 5,10-dihydroindeno[1,2-b]indole (2.69 g, 13.1 mmol) dissolved in a minimum amount of DMSO was added. After stirring at room temperature for 1 hour, dimethyl sulphate (1.5 cm3, 15 mmol) was introduced, and stirring continued for a further 1 hour. Water (3 cm3) was cautiously added, and the reaction then poured into ice/water. The solid thus formed was collected by suction filtration, washed firstly with water, dried on the water pump, and then washed with petrol (60°-80° C.). Crystallization from ethanol yielded colourless needles of the title compound. Yield: 1.52 g (53%). M.p. 152° C. 1H NMR (CDCl3) δ: 3.55 (2H, s,), 3.85 (3H, s,), 6.8-7.4 (8H, m, arom.).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[CH:15](O)=[O:16]>>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:6]=[CH:5][C:3]=1[NH:4][CH:15]=[O:16]
Reactant: O=CO
Reactant: Cc1cc(-c2cnn(C)c2)ccc1N
Product: Cc1cc(-c2cnn(C)c2)ccc1NC=O

Procedure:
A solution of 2-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 98, 100 mg, 0.534 mmol) in formic acid (3 mL) was heated to reflux for 3 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous saturated NaHCO3 solution (30 mL) and EtOAc (30 mL). The aqueous layer was re-extracted with EtOAc (30 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5]([OH:7])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:28][C:20]1[C:21]([C:5](=[O:7])[C:4]2[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(OC)cccc2C(F)(F)F)c(OC)c1OC

Procedure:
65A (1.38 g, 0.00625 mol) is reacted with 3,4,5-trimethoxytoluene (1.14 g; 0.00625 mol) in the presence of P2O5 (5.0 g) and dichloromethane (100 ml) as described in Example 6 yielding white crystals, 1.68 g (69.8% ), mp 69-70° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24](O)=[O:25])(=[O:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccncc1N
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: COc1ccc(F)cc1-c1ccncc1NC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(5-fluoro-2-methoxy-phenyl)-pyridin-3-ylamine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 114, intermediate a) after a reaction time of 18 hours. The residue was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (40:60 to 20:80. Brown liquid (68%). MS (ESI): m/z=469.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([S:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)(=[O:27])=[O:26])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)c(C)c1
Yield: 92 %

Procedure:
Sulfonylation of 1-(2,4-dimethylphenyl)piperazine (293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base. 1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in 92% yield (539 mg) as white solid.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[C:29]1([CH3:44])[CH:34]=[CH:33][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40](Cl)=[O:41])(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[C:29]1([CH3:44])[CH:30]=[CH:31][C:32]([S:35]([O:38][C@H:39]([CH3:43])[C:40]([N:1]2[C@@H:9]3[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:3][C@H:2]2[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:41])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2[C@H](C(=O)OCc3ccccc3)C[C@@H]3CCCC[C@@H]32)cc1
Reaction time: 1 h

Procedure:
Introduce into a reactor 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane, and then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine, followed by 202 g of (1R)-2-chloro-1-methyl-2-oxoethyl p-toluenesulphonate. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water. The solution of benzyl (2S,3aS,7aS)-1-[(2R)-2-{p-toluenesulphonyloxy}propionyl]octahydro-1H-indole-2-carboxylate so obtained is used as it is in the following Step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[N+:9]([O-])([OH:11])=[O:10]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:9]([C:5]1[S:1][C:2]([C:6]([OH:8])=[O:7])=[CH:3][CH:4]=1)([O-:11])=[O:10]
Reactant: O=C(O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
2-Thiophenecarboxylic acid (6.4 g, 50 mM) was suspended in acetic anhydride (15 ml) and fuming nitric acid (16 ml) in glacial acetic acid (25 ml) added slowly over 1 hour with stirring, while keeping the temperature of the reaction mixture below 30° C. The reaction mixture was stirred at ambient temperature for 2 hours. The product was purified by subjecting to chromatography (470 ml) on HP20SS resin using methanol/(water +1% acetic acid): as eluant. The pure title compound was obtained together with a mixture of 4- and 5-nitrothiophene-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:16]1[N:17]([CH2:24][C:25]2([CH3:28])[CH2:27][O:26]2)[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>CN(C=O)C>[CH3:27][C:25]1([CH2:28][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[O:26][C:16]2=[N:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][N:17]2[CH2:24]1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(OC(F)(F)F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
4-Trifluoromethoxyphenol (198 mg, 1.11 mmol) was dissolved in DMF (5 ml). To the solution, sodium hydride (48 mg, 1.21 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 80° C. To the resulting solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (220 mg, 1.01 mmol) was added with cooling on ice-bath, and the solution was stirred for 15 minutes at 80° C. The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and then crystallized from methylene chloride-diisopropyl ether to afford 2-methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole (170 mg, yield 47%) as a white powder.
Reaction SMILES: [Na].C(O[C:5](=O)[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])C.[Br:14][C:15]1[CH:16]=[C:17]([C:20]([Br:23])=[CH:21][CH:22]=1)CBr.[OH-].[K+]>C(O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:20]([Br:23])=[CH:21][C:22]=1[CH2:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8]
Reactant: BrCc1cc(Br)ccc1Br
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Cc1cc(Br)ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1000 ml three-necked round-bottom flask equipped with a reflux condenser, dropping funnel with pressure-equalizing, and magnetic stirring bar, 6.10 g (0.27 mol) of sodium metal was dissolved in 150 ml of dry ethanol. To the resulting solution, 45.5 g (0.26 mol) of diethylmethylmalonate in 50 ml of dry ethanol was added dropwise within 10 minutes. This mixture was stirred for 15 minutes; then 84.3 g (0.26 mol) of 3,6-dibromobenzylbromide was added, while vigorously stirring, at a rate that allowed the reaction mixture to maintain a gentle reflux. Additionally, this mixture was refluxed for 4 hours, and then cooled to room temperature. A solution of 52.1 g of KOH in 140 ml of water was added. This mixture was refluxed for 3 hours to saponificate the ester formed. Ethanol and water were distilled off. To the residue, 200 ml of water, and then, 12 M HCl (to pH 1) were added. The substituted methylmalonic acid precipitated and was separated, washed with 3×100 ml of cold water, and dried overnight on watch glass. Crude 3-(2,5-dibromophenyl)-2-methylpropanoic acid was obtained after decarboxylation of this substituted methylmalonic acid by heating it in a round bottom flask for 2 hours at 160° C. Crude 3-(2,5-dibromophenyl)-2-methylpropanoic acid was used without further purification. A mixture of this acid, 70 ml of SOCl2, and 100 ml of CH2Cl2 was stirred for 3 hours at reflux. Thionyl chloride and CH2Cl2 were distilled off. The residue was dried in vacuum, and then dissolved in 95 ml of CH2Cl2. To a suspension of 47.0 g (0.35 mol) of AlCl3 in 470 ml of CH2Cl2, the above-obtained solution of 3-(2,5-dibromophenyl)-2-methylpropionyl chloride was added dropwise, while vigorously stirring, for 1 hour at −20° C. This mixture was refluxed for 3 hours, cooled to ambient temperature, and then poured on 500 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and evaporated to dryness. The crude 4,7-dibromo-2-methyl-1-indanone was purified by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, h 250 mm; eluent: hexanes/methyl-tert-butyl ether (1:1, vol.)). Yield 54.1 g (70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=2[O:18][CH3:19])[N:3]=1.COC1C(OC)=CC=CC=1CO.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:19][O:18][C:11]1[C:12]([O:16][CH3:17])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[N:3]=1
Reactant: COc1cccc(COc2cncc(Cl)n2)c1OC
Reactant: C1CNCCN1
Agent: COc1cccc(CO)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(COc2cncc(N3CCNCC3)n2)c1OC

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2,3-dimethoxybenzyl)oxy]pyrazine (2.51 g, 8.93 mmol; obtained according to the procedure of example 50, step 1, starting from 2,3-dimethoxybenzyl alcohol), piperazine (2.38 g, 27.7 mmol) and K2CO3 (1.23 g, 8.9 mmol). The yield of the title compound was 1.66 g (56%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 331 (M+H)+. HRMS m/z calcd for C17H22N4O3 (M)+ 330.1692, found 330.1690.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C=O)C>[CH3:19][N:20]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:9]=2)=[CH:33][CH:34]=1)[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cncc(/C=C/C(=O)Nc3ccc(CN(C)C4CCOCC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
To a solution of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg), 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (168 mg) and triethylamine (0.10 ml) in DMF (10 ml) was added diethyl cyanophosphate (0.12 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To the residue was added water, the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:2) to give (E)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic amide (Compound 215) (24 mg) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:13][C:12]([OH:15])([CH3:14])[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: Cn1ncc(N)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Intermediate 44, tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.20 mmol) in MeOH (5 mL), was added 10% palladium on carbon (10 mg) and the mixture was stirred under an atmosphere of H2 (60 psi) for 16 hr. The mixture was filtered through Celite® and the solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as an oil. To a solution of this amine in DCM (5 mL), DIPEA (0.1 mL, 9.6 mmol), PyBOP (0.16 g, 0.3 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (78 mg, 0.22 mmol) were added and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL) and washed with water (10 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a solid (122 mg). To this solid (122 mg, 0.18 mmol) in MeOH (1 mL), a solution of HCl (4 M in 1,4-dioxane, 3.2 mL, 12.9 mmol) was added and the resulting solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. Purification by preparative HPLC gave 190 as an off-white solid (40 mg, 44% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.19 (s, 1H), 8.24 (s, 1H), 7.59-7.48 (m, 3H), 7.33-7.23 (m, 2H), 3.69 (s, 3H), 3.26-3.02 (m, 4H), 2.98-2.73 (m, 4H), 1.01 (s, 3H). Alkyl NH and OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncc(Cl)cn1
Yield: 48.6 %

Procedure:
(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API+): Found 213 (MH+−tBoc). C14H2135ClN4O2 requires 312.