Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[P:11]([OH:14])([OH:13])[OH:12].P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[CH:5]1[CH:6]=[N:1][CH:2]=[C:3]([CH2:7][C:8]([P:11]([OH:14])([OH:13])=[O:12])([P:11]([OH:14])([OH:13])=[O:12])[OH:10])[CH:4]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: OP(O)O
Solvent: Clc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C(O)(Cc1cccnc1)P(=O)(O)O
Temperature: 87.5 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Pyridine acetic acid (25 g) in 500 ml of chlorobenzene added to phosphorous acid (35.5 g). The reaction mixture was heated up to 85-90° C. To the reaction mixture phosphorous trichloride (58.97 g) was added slowly to obtain a yellowish rigid, thick mass. The reaction mass was cooled to ambient temperature. The solvent was decanted. Demineralized water (200 ml) was added to the reaction mass and refluxed azeotropically, to remove residual chlorobenzene. Filtered through hyflo bed while hot, washed with hot demineralized water. The reaction mass was cooled to 0-5° C., stirred for 1.0 hour, filtered the solid and washed to get risedronic acid (30.0 g, yield 58%) having purity of 83.98% by HPLC.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].C(N(CC)CC)C>C(#N)C>[O:30]=[C:29]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:13]2[CH2:14][CH2:15][C:16](=[O:17])[C:12]=2[CH:3]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[NH:2]1
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)-methyl)benzonitrile hydrochloride (intermediate 13, 11.8 g, 26.1 mmol based on 90% purity) in acetonitrile (100 mL) and 1,1′-carbonyldiimidazole (5.28 g, 32.6 mmol) is treated with triethylamine (0.9 mL, 6.5 mmol), and the mixture is stirred at room temperature for 1 h. All volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered, washed with water and dried. The residue is purified by recrystallization from hot toluene (130 mL). Yield: 8.6 g; ESI mass spectrum [M+H]+=398; Retention time HPLC: 1.06 min (V011_S01). LH4BRM00213
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[O:32]=[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][NH:34]1>>[CH3:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:37]=[CH:38][C:33](=[O:32])[NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: O=c1ccc(B(O)O)c[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamide and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.3 min, m/z=524 (M+1); 1H NMR (CDCl3) 7.81 (d, 1H, J=9 Hz), 7.63 (br s, 1H), 7.39-7.31 (m, 5H), 7.18 (d, 2H, J=8 Hz), 7.03 (d, 2H, J=7 Hz), 6.79 (d, 1H, J=9 Hz), 5.67 (q, 1H, J=6 Hz), 2.93 (s, 3H), 2.90 (m, 1H), 2.49 (d, 1H, J=15 Hz), 2.32 (d, 1H, J=15 Hz), 2.28-2.18 (m, 3H), 1.54 (d, 3H, J=7 Hz), 1.36 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[N+:11]([C:14]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:24])([O-:13])=[O:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:23][C:20]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[C:15]2[C:19]=1[C:18](=[O:24])[CH2:17][CH2:16]2)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCc2c([N+](=O)[O-])ccc(O)c21
Reactant: CCCSP(=O)(Cl)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OCC)Oc1ccc([N+](=O)[O-])c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Ethyl S-propyl chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-nitro-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product, O-ethyl S-propyl O-(4-nitroindan-1-on-7-yl) thiophosphate.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:44])[N:25]([CH2:42][CH3:43])[C:26]4[CH:27]=[CH:28][C:29]5[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=5[CH:41]=4)[CH2:21][C@@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.FC(F)(F)C([O-])=O.[C:53](Cl)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>CC#N>[CH2:42]([N:25]([C:26]1[CH:27]=[CH:28][C:29]2[O:34][CH2:33][C:32](=[O:35])[N:31]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:30]=2[CH:41]=1)[C:24]([C@H:22]1[CH2:21][C@@H:20]([NH:45][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:19][NH:18][CH2:23]1)=[O:44])[CH3:43]
Reactant: CCN(C(=O)[C@H]1C[C@@H](N)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Product: CCN(C(=O)[C@@H]1CNC[C@H](NC(=O)C(C)(C)C)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{ethyl-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, trifluoroacetate and pivaloyl chloride. MS: 475.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.29 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]([NH2:32])=O)=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[S:25][C:26]([C:30]#[N:32])=[C:27]([CH3:29])[N:28]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(N)=O)s3)cc12
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C#N)s3)cc12
Yield: 79.4 %

Procedure:
A solution of tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.33 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) in N,N-dimethylformamide (10 mmol) was stirred for 1 h at 0° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(5-cyano-4-methyl-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.25 g, 80.6%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)cc(F)c2OC)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(3,5-difluoro-2-methoxy-phenyl)-methanone (Example 380) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3,5-difluoro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 442.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6.04 g (0.03 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 3.04 g (0.03 mol) of triethylamine, and 30 ml of methylene chloride was cooled to approximately 0° C. To this mixture was added a solution of 3.14 g (0.03 mol) of methacryloyl chloride in 15 ml of methylene chloride over approximately 5 minutes. The mixture was stirred for an additional 15 minutes and filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The solid residue was recrystallized from 1:1 hexane:1,2-dichloroethane. The yield of N-(4-methacryloyloxybenzyl)methanesulfonamide was 3.0 g (37.13 percent of theory), m.p.=101° to 102.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:12][C:13]2[CH2:14][CH2:15][O:16][C:17]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:18]=3[C:19]=2[N:20]=1)=S.O.[NH2:27][NH2:28].[CH3:29]O>>[Br:25][C:23]1[CH:22]=[CH:21][C:18]2[C:19]3[N:20]=[C:11]([C:9]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[CH:29]=[N:28][N:27]=4)[S:12][C:13]=3[CH2:14][CH2:15][O:16][C:17]=2[CH:24]=1
Reactant: CO
Reactant: NN
Reactant: S=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: O
Product: Clc1ccccc1-n1cnnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbothioic acid (2-chloro-phenyl)-amide (160 mg), methanol (10 mL) and hydrazine hydrate (170 μL) was heated to reflux for 6 hours. The reaction mixture was then cooled and the solid collected by filtration. A mixture of this solid (144 mg) and triethyl orthoformate (5 mL) was heated to 90° C. for 2 hours and then to 130° C. for 2 hours. The reaction mixture was then cooled and the solvent removed in vacuo and the residue purified using flash chromatography to yield 314 (55 mg). NMR: (CDCl3): 3.32 (2H, t), 4.36 (2H, t), 6.96 (1H, dd), 7.11-7.16 (2H, m), 7.49-7.68 (4H, m), 8.30 (1H, s). MS: (ESI+) MH+ 461
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[S:20])[CH3:17]>CC(C)=O>[ClH:11].[CH2:16]([N:18]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:20][C:19]1=[N:21][CH:22]([CH3:24])[CH3:23])[CH3:17]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCNC(=S)NC(C)C
Solvent: CC(C)=O
Product: CCN1C(=NC(C)C)SCC1(O)c1ccc(Cl)c(S(N)(=O)=O)c1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.92 g of 1-ethyl-3-isopropylthiourea were heated in 40 ml of acetone for 15 minutes to 40° C, the mixture was stirred for another 30 minutes at room temperature and the crystals were filtered.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16](Cl)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.O1CCCC1.[NH:41]1[CH2:46][CH2:45][CH:44]([O:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:43][CH2:42]1>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[C:14](=[O:19])[C:15]=2[C:16]([N:41]2[CH2:42][CH2:43][CH:44]([O:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:46]2)=[O:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: Cn1c(-c2ccc(C(C)(C)C)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COC1CCN(C(=O)c2c(-c3ccc(C(C)(C)C)cc3)n(C)n(-c3ccc(C#N)cc3)c2=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28.5 %

Procedure:
A mixture of 3.5 g of 3-(4-t-butylphenyl)-4-chlorocarbonyl-1-(4-cyanophenyl)-2-methyl-2H-pyrazol-5-one, 1.8 g of triethylamine, 50 ml of tetrahydrofuran, 20 ml of N,N-dimethylformamide and 2.38 g of ethyl 4-piperidinoxyacetate was stirred at room temperature for 20 hours. The reaction solution was evaporated under reduced pressure, and after addition of water, the resulting residue was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride successively and dried over sodium sulfate. The insolubles were filtered off, and then the solvent was removed by evaporation. The resulting residue was purified by silica gel chromatography (eluent; ethyl acetate/chloroform=1:1) to give 1.38 g of the title compound as a colorless amorphous solid.
Reaction SMILES: C(Cl)CCl.[S:5]1(=[O:12])(=[O:11])[CH:9]=[CH:8][C:7](=[O:10])[NH:6]1.[CH3:13][C:14]([C:16]([CH3:18])=[CH2:17])=[CH2:15]>CCOCC>[CH3:13][C:14]1[CH2:15][CH:8]2[C:7](=[O:10])[NH:6][S:5](=[O:12])(=[O:11])[CH:9]2[CH2:17][C:16]=1[CH3:18]
Reactant: O=C1C=CS(=O)(=O)N1
Reactant: C=C(C)C(=C)C
Solvent: ClCCCl
Solvent: CCOCC
Product: CC1=C(C)CC2C(C1)C(=O)NS2(=O)=O

Procedure:
A 40 ml solution of ethylene dichloride containing 5.3 g (0.04 mole) of 4-isothiazolin-3-one 1,1-dioxide and 3.3 g (0.04 mole) of 2,3-dimethyl-1,3-butadiene is heated at 45°-50° C. overnight. The golden solution is cooled and concentrated to give an oil. Trituration of the oil with ether gives a white solid, 7.7 g (80%), m.p. 110°-112° C., which can be recrystallized from ethyl acetate.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]>C(O)(=O)C>[CH3:3][O:4][C:5]([C:7]1[C:16]2[C:11](=[C:12]([Br:1])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Yield: 67.6 %

Procedure:
A solution of bromine (26.6 g, 0.167 mole) in glacial acetic acid (25 ml) was added dropwise to a cooled suspension of 6-methoxy-1-naphthalenecarboxylic acid methyl ester (30 g, 0.13 9 moles) in glacial acetic acid (2.75 ml). The precipitate was collected, washed with water and crystallized from ethanol to give 33.3 g of 5-bromo-6-methoxy-1-naphthalenecarboxylic acid methyl ester; mp 119° C.; NMR (CDCl3) δ3.97 (s, 3H), 4.03 (s, 3H), 7.35 (d, J=9.25 Hz, 1H), 7.4 (m, 1H), 8.05 (d, J=6.75 Hz, 1H), 8.45 (d, J=8.25 Hz, 1H), 8.9 (d, J=9.25, 1H). The latter ester (10.1 g, 34 mmoles) and Cu2 (CN)2.H2O (3.4 g, 17 mmoles) in distilled dimethylformamide (75 ml) containing 15 drops of pyridine was heated at 180° C. for 5 hr. The hot mixture was poured into a mixture of ice (50 g) and conc. NH4OH (50 ml). The resulting precipitate was collected, washed with water, dried and recrystallized from chloroform-ethyl acetate to afford 5.6 g of 5-cyano-6-methoxy-1-naphthalenecarboxylic acid methyl ester: mp 210°-211° C., NMR (CDCl3) δ3.95 (s, 3H), 4.15 (s, 3H). To a stirred solution of the latter ester (5.95 g, 24.66 mmoles) in 2-methoxyethanol (100 ml) at 20°-22° C., 4 N aqueous NaOH solution (12.3 ml) was added. The reaction mixture was stirred at 20°-22° C. for 60 hr, diluted with water, cooled to 0° C. and rendered acidic with 1 N aqueous HCl. The precipitate was collected and dried to yield 5.6 g of the title compound; mp>290° C.; NMR (DMSO-d6) δ4.1 (s, 3H), 8.1 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH2:72])=[N:68]2)[CH2:63][O:62]1>CN(C)C=O.C(OCC)(=O)C>[CH3:60][C:61]1([CH3:73])[O:65][C@H:64]([CH2:66][N:67]2[CH:71]=[CH:70][C:69]([NH:72][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:68]2)[CH2:63][O:62]1
Reactant: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.51 g, 1.59 mmol) in N,N-dimethylformamide (6.14 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.79 mL, 4.79 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1.06 g, 2.39 mmol) and a solution of 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.33 g, 1.67 mmol) in N,N-dimethylformamide (0.5 mL). The reaction was stirred at 25° C. over the weekend. At this time, the reaction was diluted with ethyl acetate (75 mL) and was washed with a saturated aqueous ammonium chloride solution (1×150 mL), a saturated aqueous sodium bicarbonate solution (1×150 mL) and a saturated aqueous sodium chloride solution (1×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 50-100% ethyl acetate/hexanes) afforded (S)-2-[4-(2-fluoro-5-methyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.70 g, 88%) as an orange solid: HR-ES-MS m/z calculated for C26H33N4O5F [M+H]+ 501.2508, observed 501.2507; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.24 (s, 3H), 1.30 (s, 3H), 1.35-1.64 (m, 2H), 1.66-1.86 (m, 1H), 2.31 (s, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.96-4.14 (m, 3H), 4.20 (d, J=18.4 Hz, 1H), 4.30-4.40 (m, 1H), 4.59 (d, J=18.4 Hz, 1H), 4.83-4.93 (m, 2H), 6.43 (d, J=2.1 Hz, 1H), 7.08-7.20 (m, 1H), 7.27-7.38 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 10.80 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24]C3C=CN=CC=3F)[C:5]2=[N:6][CH:7]=1.[CH2:32]([C:35]([F:38])([F:37])[F:36])[CH2:33][NH2:34]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:34][CH2:33][CH2:32][C:35]([F:38])([F:37])[F:36])[C:14]4[C:19]([CH3:20])([CH3:21])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:7]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][N:6]=3)[C:5]2=[N:6][CH:7]=1
Reactant: NCCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccncc4F)c4ncc(F)cc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.186 mmol, approx. 66% purity) of the compound obtained in example 28A was dissolved in 1-methyl-2-pyrrolidone (3.6 ml) in a reaction vessel suitable for a microwave and 0.9 ml of 3,3,3-trifluoropropyl-1-amine was added. Then it was sealed with a corresponding septum and it was heated in the microwave at 150° C. for 3 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 33 mg of the title compound was obtained (34% of theor.).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19]([O-:21])=O)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][C:10]([C:19](=[O:21])[N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:30])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(C(=O)[O-])CC(=O)N(Cc2ccccc2)C1
Reactant: CNCc1ccccc1
Product: CCOC(=O)C1(C(=O)N(C)Cc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Yield: 78.7 %

Procedure:
Monoethyl 1-benzyl-5-oxopyrrolidine-3,3-dicarboxylate (29.1 g) obtained in Preparative Example 1 (1) and N-benzyl-N-methylamine (12.1 g) were treated in the same manner as in Preparative Example 1 (2) to give 31 g of the object compound as an oil.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: OC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(Br)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.42 h
Yield: 81.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 110 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 50 mg of 3-hydroxyazetidine hydrochloride, and 100 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 25 minutes. After adding 0.5 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 101 mg of the title compound as a pale yellow powder.