Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[CH:20][CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CN(CC(C2C=CC(CO)=C([F:52])C=2)=O)C(=O)C=1)C1C=CC=CC=1.P(Br)(Br)Br>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][Br:25])=[C:20]([F:52])[CH:19]=2)=[O:17])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)c(F)c1
Agent: BrP(Br)Br
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)c(F)c1

Procedure:
4-Benzyloxy-1-[2-(4-bromomethyl-3-fluoro-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 15c from 240 mg (0.65 mmol) 4-benzyloxy-1-[2-(3-fluoro-4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 16g) and 0.43 mL (4.57 mmol) phosphorus tribromide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Br)([Br:18])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=S(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: BrCc1cccc(Oc2ccccc2)c1
Yield: 81.3 %

Procedure:
A solution of 3-phenoxybenzyl alcohol (36.0 grams, 0.18 mole) in toluene (95 ml) was added dropwise during a thirty minute period to a stirred solution of thionyl bromide (50 grams, 0.24 mole), pyridine (0.5 gram) and toluene (175 ml) while maintaining the temperature below 30° C. After the addition was complete,the reaction mixture was heated at 50°-60° C. for two hours. Upon cooling, the reaction mixture was concentrated under reduced pressure leaving a residue. This residue was dissolved in toluene (200 ml) and washed with water (10×100 ml) until a neutral pH was obtained. The dried (magnesium sulfate) toluene layer was concentrated under reduced pressure leaving a residue. This residue was distilled yielding 38.5 grams of 3-phenoxybenzyl bromide, b.p. 120°-144° C./0.05 mmHg. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][C:25]1[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][C:25]1[C:26]([O:31][CH3:32])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COc1ncccc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ncccc1Cn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 30.3 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 476 mg, 1.56 mmol), 3-chloromethyl-2-methoxy-pyridine (Intermediate 51; 989 mg, 6.3 mmol) and tetrabutylammonium iodide (580 mg, 1.6 mmol) in dimethylformamide (16 mL) was heated at 100° C. for 48 h. The solvent was evaporated and dichloromethane (250 mL) was added. The solution was washed with concentrated aqueous sodium thiosulfate (2×100 mL), saturated aqueous sodium hydrogen carbonate (100 mL), water (6×500 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated and purified using a Biotage 40L system, eluting with 1-2% methanol/dichcloromethane to give an oily material. This material was dried on a vacuum pump, co-evaporated three times with ethanol, and finally held again under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-(2-methoxy-pyridin-3-ylmethyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (201 mg, 30%) as an off-white solid. ES(+)-MS (M+H) 426.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17](O)[CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:27])CC>ClCCl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([F:27])[CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a mixture of S)-2-((R)-3-hydroxy-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 2.8 mmol) in dichloromethane (5 mL) at −78° C., was added slowly DAST (0.4 mL, 3 mmol). After stirring at room temperature for 3 h, the reaction mixture was diluted with methanol and concentrated. The residue was dissolved in EtOAc and washed with sodium bicarbonate solution (3×), sodium chloride (1×). After concentrating, the residue was purified to give 700 mg (87%) of (S)-2-((R)-3-fluoro-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[O:20]1[C:24]2([CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]3[CH:19]=[CH:18][C:9]4[O:10][C:11]5[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=5[C:8]=4[CH:7]=3)=[O:4])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(CN1CCC2(CC1)OCCO2)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 46.2 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), 1,4-dioxa-8-azaspiro(4.5)decane (0.072 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided 2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.080 g) as its trifluroacetic acid salt after reverse-phase HPLC purification.MS (ESI) m/z 385 ([M+H]+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)cc(F)c1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)cc(F)c1
Yield: 33.8 %

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 780 mg of 3,5-difluoroaniline in place of the 2-fluoroaniline. 133 mg of N-(3,5-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=O.C[Si]([C:26]#[N:27])(C)C.FC(F)(F)C(O)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[C:26]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:27]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl 1,2,3,4-tetrahydro 1-naphthalenone, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture was heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p toluene sulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a colorless oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109°-110° C.
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:11]=[C:10]([N:12]2[CH2:43][CH2:42][C:15]3[N:16]=[C:17]([C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[C:24]([CH3:41])=[CH:25][N:26]5[S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[N:18]=[C:19](OC)[C:14]=3[CH2:13]2)[N:9]([CH3:44])[N:8]=1)([CH3:6])[CH3:5].[ClH:45].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:45][C:19]1[C:14]2[CH2:13][N:12]([C:10]3[N:9]([CH3:44])[N:8]=[C:7]([CH:4]([CH3:5])[CH3:6])[CH:11]=3)[CH2:43][CH2:42][C:15]=2[N:16]=[C:17]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24]([CH3:41])=[CH:25][N:26]3[S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=2)(=[O:32])=[O:33])[N:18]=1
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 87 °C

Procedure:
Ethanol (1.8 mL) was added to 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (195 mg, 0.342 mmol) followed by 12 N aqueous hydrochloric acid (1.8 mL, 21.8 mmol). The mixture was then heated to 87° C. for ca. 15 hours. The mixture was then cooled to room temperature, diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried by passing through a phase separator and then concentrated. The resulting residue was diluted with 1,2-dichloroethane (3.5 mL) and place at 0° C. Then N-chloromethylene-N,N-dimethyl ammonium chloride (Vilsmeier reagent) (85 mg, 067 mmol) was added. The resulting mixture was then heated to 35° C. After 5 minutes at 35° C. the mixture was diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated to furnish 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 575.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17](O)=[C:16]([Cl:22])[C:15]=1[OH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)(Cl)Cl>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([O:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:16]([Cl:22])[C:15]=1[OH:23]
Reactant: CN1CCN(CCO)CC1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1O
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(OCCN2CCN(C)CC2)c(Cl)c1O
Reaction time: 16 h

Procedure:
To a solution of 2-(4-methylpiperazin-1-yl)ethanol (14.42 g) and 3,5-dichloro-2,4-dihydroxybenzoic acid methyl ester (52.15 g) in chloroform (400 ml) were added triphenylphosphine (28.85 g) and azodicarboxylic acid diisopropyl (21.7 ml) at room temperature, and the mixture was stirred for 16 hours. 1N Hydrochloric acid (300 ml) was added to the reaction mixture for extraction to give a crude product of the title compound.
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O[CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[CH2:38]([N:40]([CH2:74][CH3:75])[CH2:41]/[CH:42]=[CH:43]\[C:44]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=1[S:51]([CH2:54][C:55]1[C:60]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[C:59]([OH:68])[C:58]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:57][CH:56]=1)(=[O:53])=[O:52])[CH3:39].BrCC#N>>[C:24]([CH2:23][O:68][C:59]1[C:58]([C:69]2[CH:73]=[CH:72][O:71][CH:70]=2)=[CH:57][CH:56]=[C:55]([CH2:54][S:51]([C:45]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:44]=2/[CH:43]=[CH:42]\[CH2:41][N:40]([CH2:38][CH3:39])[CH2:74][CH3:75])(=[O:52])=[O:53])[C:60]=1[C:61]([O:63][C:64]([CH3:66])([CH3:67])[CH3:65])=[O:62])#[N:25]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(O)c1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: N#CCBr
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OCC#N)c1C(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from (Z)-tert-butyl 6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 194) and bromoacetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH:20]2[NH:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH:13]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:25]2[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21][CH:20]2[CH2:19][NH:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(CNc2cccnc2)C1
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2CNc2cccnc2)cc1
Reaction time: 1 h

Procedure:
4-Methoxyphenyl isocyanate (85 mg, 0.567 mmol) was added to a solution of tert-butyl 3-((pyridin-3-ylamino)methyl)piperazine-1-carboxylate (166 mg, 0.567 mmol) in CH2Cl2(4 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, and the material was purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 81.7 mg (26%) of the TFA salt of the title compound as a white solid. LC-MS: RT=5.29 min, [M+H]+=442.2.
Reaction SMILES: [NH2:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Product: COC(=O)c1ccc(C(C)(C)N2CCCS2(=O)=O)cc1

Procedure:
Using methyl 4-(1-amino-1-methylethyl)benzoate (570 mg) and 3-chloropropane-1-sulfonyl chloride (0.47 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (862 mg) was obtained.
Reaction SMILES: [Li+].[OH-:2].O.OO.C([C@@H]1COC(=O)N1[C:19](=[O:41])[C@@H:20]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH2:21][N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])C1C=CC=CC=1>C1COCC1>[C:25]([O:24][C:23]([N:22]([CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:21][C@H:20]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:19]([OH:41])=[O:2])=[O:29])([CH3:27])([CH3:26])[CH3:28]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1

Procedure:
LiOH (1.41 g, 33.5 mmol) was added to a flask containing THF (360 mL) and H2O (120 mL), which was stirred until dissolved. At this point, the reaction was cooled to 0° C. with ice, and hydrogen peroxide (35 wt. %, 6.52 g) was added. This solution was stirred for 10 minutes, at which point tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (8.6 g, 16.8 mmol) was added as a solution in THF (20 mL). The reaction was stirred overnight with warming. The reaction was quenched by the addition of 10% aqueous Na2SO3 (1 mL) and saturated aqueous NaHCO3 (1 mL) and stirred for 10 minutes. The reaction was concentrated to remove THF and the aqueous layer extracted with ether (3×). The aqueous layer was diluted with EtOAc and acidified with 1N HCl. The organic layer was removed, and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried with MgSO4 and concentrated to give the crude product, (S)-3-( tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid as a clear oil (LCMS (APCI+) [M-Boc+H]+ 254.1; Rt: 3.03 min).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[Na+]>C(O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][OH:13])=[CH:6][CH:7]=1
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(CO)c1ccc(F)cc1

Procedure:
2 g of 2-bromo-1-(4-fluorophenyl)ethanone, and 6 eq of sodium formate in 15 mL of Ethanol/Water are irradiated under microwave for 5 min at 150° C., 11 bars. After filtration and evaporation of ethanol, water is added. The expected product is isolated by filtration
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[N:5]2[N:22]=[CH:23][CH:24]=[C:4]2[N:3]=1.O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]2)[N:5]2[N:22]=[CH:23][C:24]([CH:33]=[O:34])=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3ccnn23)CC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc3c(C=O)cnn23)CC1
Reaction time: 8 h
Yield: 48 %

Procedure:
To tert-butyl 4-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate (1.7 g, 4.8 mmol) in DMF (36 mL), POCl3 (7.7 mL, 82.9 mmol) was added dropwise at room temperature. After the addition was complete, the reaction was stirred for 8 hours. Then, the reaction was quenched by slow addition to ice cold 6N NaOH. The mixture was diluted with water and the solid was collected by filtration. The solid was washed several more times with water then dried under vacuum overnight. The product, tert-butyl 4-(5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-ylamino)piperidine-1-carboxylate, was collected as a solid in 48% yield. LCMS (M+1=380)
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])=[CH2:11])=[CH:6][N:7]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: C[Mg]Br
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A lanthanum(III) chloride-bis(lithium chloride) complex (0.6 M solution in THF, 16.7 mL, 10 mmol) was added to a solution of 1-(6-bromopyridin-3-yl)ethanone (2 g, 10 mmol) in THF (10 mL), and the mixture was stirred at room temperature for 1 hour. Methyl magnesium bromide (1.12 M solution in THF, 10.7 mL, 12 mmol) was added thereto at 0° C., and the mixture was stirred for 1 hour. A 10% citric acid aqueous solution was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and insoluble matter was filtered off through Celite. After extraction with ethyl acetate twice, combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. An internal salt of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (2.86 g, 12 mmol) was added to a solution of the obtained residue in THF (20 mL), and the mixture was stirred at 60° C. for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=98/2-80/20 (gradient)] to obtain the title compound (1.00 g, yield: 51%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](S(C)(=O)=O)[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4].[NH3:16]>O1CCOCC1.CO>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:16])[N:8]=[C:7]([Cl:15])[N:6]=1)=[O:4]
Reactant: N
Reactant: COC(=O)c1cc(S(C)(=O)=O)nc(Cl)n1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
2-Chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl ester (3.7 g, 14.75 mmol) was dissolved in dioxane and 7N ammonia in methanol was added. The reaction mixture was stirred at room temperature for 3 hours, concentrated under vacuum, and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated. The product was purified by column chromatography to provide 6-amino-2-chloropyrimidine-4-carboxylic acid methyl ester (2.35 g, 85% yield): 1H NMR (DMSO-d6): δ 7.6 (br s, 1H), 7.00 (s, 1H), 3.84 (s, 3H), 3.33 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][CH2:15]Cl)[CH3:12]>>[CH2:11]([O:13][CH2:14][CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])[CH3:12]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CCOCCCl
Product: CCOCCn1c(C)nc2ccccc21
Yield: 82 %

Procedure:
1-(2-Ethoxyethyl)-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole, and an equimolar amount of 2-chloroethyl ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 82%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15]C)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:8][C:6]1[CH:5]=[C:4]([CH:9]2[N:26]([CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:27])[C:13](=[O:15])[C:12]([CH3:18])([CH3:17])[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(C)(C)NCC(=O)c1cc(F)cc(F)c1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)C(C)(C)NCC1c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-methylpropanoate from Step A (8.60 g, 31.7 mmol), glycine ethyl ester hydrochloride (44.3 g, 317 mmol), and AcOH (5.71 mL, 95 mmol) in MeOH (300 mL) was stirred at ambient temperature for 10 min. NaCNBH3 (2.39 g, 38.0 mmol) was added and the pH of the mixture was checked and adjusted to pH ˜5 as necessary. The reaction mixture was heated to 50° C. for 18 h. Additional AcOH (4 mL) was added and the reaction mixture was heated to 60° C. for 6 h then allowed to cool and concentrated in vacuo to a volume of ca. 150 mL. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (300 mL) and then extracted with CH2Cl2 (1 L). The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=327 (M+1).