Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1.[CH2:23]([SH:25])[CH3:24].O>CN1C(=O)CCC1>[CH2:23]([S:25][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([S:18][C:19]([F:22])([F:21])[F:20])=[CH:14][C:12]=2[N:13]=1)[CH3:24]
Reactant: FC(F)(F)Sc1ccc2oc(-c3sccc3Br)nc2c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1ccsc1-c1nc2cc(SC(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.31 g of sodium hydride (60%) was added to 20 ml of a solution of 2.76 g of 2-(3-bromothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole and 0.6 ml of ethanethiol in NMP at 0° C., and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous hydrochloric acid solution and a saturated aqueous salt solution and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 2.65 g of 2-(3-ethylthiothiophen-2-yl)-5-(trifluoromethylthio)benzoxazole (Compound of Present Invention (30)).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pd].C(O)C.O1CCCC1>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCOCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)N1CCOCC1
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of 1-(morpholinylsulfonyl)-2-nitrobenzene (5.18 g, 19 mmol); as prepared in the preceding step, and 10% palladium on carbon (520 mg) in ethanol (80 mL) and tetrahydrofuran (80 mL) was stirred under hydrogen (balloon) for 5 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated to give the title compound as a yellow solid (4.50 g, 98%) which was directly used for the next step without further purification.
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:20][CH3:21])=[N:12][C:13]([CH3:19])=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])[C:11]([O:20][CH3:21])=[N:12][C:13]=1[CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C(C)C)cc1NC(=O)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc(C(C)C)c(C)nc2OC)CC1
Yield: 64 %

Procedure:
Phenyl-N-(5-isopropyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([O:19][C:20]1[CH:21]=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)=[N:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:8]([O:19][C:20]1[CH:25]=[N:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:4][C:3](=[O:5])[C@@H:2]([CH3:1])[CH2:6][CH3:7])=[CH:28][CH:27]=2)=[N:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCC(C)C(=O)O
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(OC(=O)[C@@H](C)CC)cc2)nc1
Yield: 70 %

Procedure:
Pour 0.328 g of 2-methylbutanoic acid synthesized from (s)-amylalcohol ([α]D23 -5.8° (neat)), 1.1 g of 4-(5-n-undecyloxy-2-pyrimidinyl)phenol, 8 ml of anhydrous chloroform and 0.662 g of 4-dimethylaminopyridine, S,S'-dicyclohexylcarbodimide into a 25 ml flask and allow to react for one whole day at room temperature. After the reaction, filter and separate the insoluble matters, and extract the reaction product with chloroform. The organic layer is washed with water, 2N hydrochloric acid and water, dried and evaporated to remove the organic solvent. The reaction product is purified with silica gel chromatography and re-crystallized crystal, and then optically active (s)-5-n-undecyloxy-2-[4-(2-methylbutanoyloxy)phenyl]pyrimidine is obtained at a yield of 70%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][C@H:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][C@H:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 95 %

Procedure:
In a manner similar to that described in example 571, from from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (38 mg, 0.089 mmol) and (2R)-2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (40 mg, 95% yield) as a white solid. Analytical data was identical to example 571.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][C:7]#[C:8][CH2:9][Br:36]
Reactant: OCC#CCOCc1cc(Br)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COCC#CCBr
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)-but-2-ynyl alcohol (8.9 g, 32.6 mmol) in diethyl ether (109 ml) was treated with triphenylphosphine (11.1 g, 42.4 mmol) and carbon tetrabromide (14.1 g, 42.4 mmol). The cloudy solution was stirred at ambient temperature for about 14 hours. The precipitate was removed by filtration and the filtrate was concentrated. The desired title intermediate was purified from the filtrate by flash chromatography. Yield 9.83 grams (90%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[F:18][C:19]([F:31])([F:30])[S:20]([C:23]1[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:19]([F:18])([F:31])[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=2)[O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: O=C(O)c1ccc(Oc2cccc(O)c2)cc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(Oc2cccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-(3-hydroxyphenoxy)benzoic acid (100 mg, 0.434 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (106 mg, 1 equiv.) and potassium carbonate (240 mg, 4 equiv.) in DMF was heated to 100° C. overnight. The reaction was poured into water, extracted with EtOAc, washed the organic layer with water, brine, dried and concentrated. The residue was column chromatographed to give 4-[3-(4-trifluoromethanesulfonyl-phenoxy)-phenoxy]-benzoic acid. 1HNMR (300 MHz, DMSO-d6) δ 8.09 (d, J=8.97 Hz, 2H), 7.95 (d, J=8.94 Hz, 2H), 7.56 (t, J=8.54 Hz, 1H), 7.33 (d, J=8.94 Hz, 2H), 7.10 (d, J=8.97 Hz, 2H), 7.04-7.11 (m, 3H). MS-EI m/z 438 [M+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14])(=O)[CH3:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:8][C:7]1[C:2]2=[N:1][C:9]([CH3:10])=[C:12]([CH2:17][CH2:16][OH:15])[C:13](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1O
Reactant: CC(=O)C1CCOC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1nc2c(O)cccn2c(=O)c1CCO

Procedure:
According to the U.S. Pat. No. 5,688,799 (hereinafter referred to as the '799 patent), the compound of formula I is prepared by the reaction of 2-amino-3-hydroxypyridine with 2-acetylbutyrolactone in the presence of p-toluenesulfonic acid in xylene solvent at reflux temperature for overnight using a water separator to yield 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is converted into its hydrochloride salt, followed by reaction with thionyl chloride in dimethylformamide to produce 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1)#[CH:13]>>[C:14]1([C:12]#[C:13][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: C#CC1=CCCCC1
Product: C(#Cc1ccc2ccccc2c1)C1=CCCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 99 %

Procedure:
Following the general procedure using 2-bromonaphthalene (103 mg, 0.50 mmol) and 1-ethynylcyclohex-1-ene (100 μL, 0.85 mmol), the reaction was stirred for 21 h at rt. Column chromatography on silica gel (eluting with 1% EtOAc/hexanes) afforded the product as an off-white solid (115 mg, 99%).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][CH:25](Cl)[CH3:26])[CH3:23]>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([O:15][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)Cl
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1
Solvent: ClCCl
Product: CCOC(C)OC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1

Procedure:
reacting said N-benzoyl-3-phenyl-isoserine with 1-chloroethyl ethyl ether and tertiary amine in methylene chloride to form-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine for the C13 side chain;
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:34][C:35]1[N:36]=[CH:37][C:38]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])=[CH:39][CH:40]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: OB(O)c1ccc(Cl)nc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCOCC2)CC1
Yield: 31 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (31%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:31]=[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:31]=[C:32](/[C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)\[CH3:33])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: COc1ccc(C(C)=CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (43 mg, 0.184 mmol) was dissolved in DMF (4 mL) Copper (I) iodide (4 mg, 0.0184 mmol) L-proline (4.2 mg, 0.037 mmol) and K3PO4 (78 mg, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (50 mg, 0.22 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (DMSO-d6, Oxalate salt) δ (ppm): 7.60 (m, 3H), 7.10 (m, 2H), 6.98 (m, 3H), 3.80 (s, 3H), 3.60 (m, 4H), 3.10 (m, 4H), 2.82 (s, 3H), 1.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:10]1=[O:42].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH:75]1[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]1>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:31])[C:16](=[O:30])[C:17]([CH3:29])=[C:18]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([N:75]4[CH2:79][CH2:78][CH:77]([OH:80])[CH2:76]4)=[O:25])[CH:21]=3)[C:13]=2[C:12](=[O:32])[N:11]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:10]1=[O:42]
Reactant: OC1CCNC1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)O)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)N5CCC(O)C5)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoic acid (2b) (800 mg, 1.172 mmol) in THF (5 ml) was added EDC.HCl (494 mg, 2.58 mmol), HOBT (395 mg, 2.58 mmol), DIPEA (0.819 ml, 4.69 mmol) and pyrrolidin-3-ol hydrochloride (290 mg, 2.35 mmol). The reaction mixture was stirred at room temperature under N2 atm for 6 h. The reaction mixture was then partitioned between water and ethyl acetate. Organic phase was removed, washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuop to afford crude 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (2c) (550 mg) which was carried forward for the next step without further purification.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:25][CH2:24][C:13]2([CH:15]([NH:16]C(OC(C)(C)C)=O)[CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[NH2:26][C:27]1[C:36]([F:37])=[C:35](F)[C:34](C)=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:26][C:27]1[C:36]([F:37])=[C:9]([N:11]2[CH2:25][CH2:24][C:13]3([CH:15]([NH2:16])[CH2:14]3)[CH2:12]2)[C:34]([CH3:35])=[C:33]2[C:28]=1[C:29](=[O:47])[C:30]([C:44]([OH:46])=[O:45])=[CH:31][N:32]2[C@@H:40]1[CH2:42][C@@H:41]1[F:43]
Reactant: CC(C)(C)OC(=O)NC1CC12CCN(C(=O)OCc1ccccc1)C2
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(N2CCC3(CC3N)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 155 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A 693 mg (2.00 mmol) portion of 5-benzyloxycarbonyl-1-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (1-a) was dissolved in 60 ml of ethanol, and the solution was mixed with 600 mg of 10% palladium-carbon and subjected to 2 hours of hydrogenation under atmospheric pressure. After completion of the reaction, 10% palladium-carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was suspended in 6 ml of dimethyl sulfoxide, and the suspension was mixed with 312 mg (1.00 mmol) of 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2.00 ml (14.35 mmol) of triethylamine, and heated at 150 to 160° C. for 19 hours in a stream of nitrogen. After evaporation of the solvent, the thus obtained residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, subsequently evaporating the solvent. The thus obtained tert-butylcarbamate compound was mixed with 5 ml of concentrated hydrochloric acid, stirred at room temperature for 20 minutes, washed with chloroform (50 ml×3), adjusted to pH 7.4 with sodium hydroxide aqueous solution and then extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a preparative TLC (developed by the lower layer of chloroform:methanol:water 7:3:1) and recrystallized from ethanol-ether to yield 142 mg (35%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c(Cl)ccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2c(Cl)ccnc12
Yield: 75 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-chloro-quinolin-8-ylamine (Intermediate 464) (1.5 g, 8.43 mmol), 2-nitrobenzene-1-sulfonyl chloride (2.43 g, 11.0 mmol), DMAP (cat), pyridine (2 ml, 25.28 mmol) in DCM (70 ml) for 3 h at room temperature gave the title compound (2.3 g, 74%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].[Cl:9][S:10](O)(=[O:12])=[O:11]>CCCCCCC>[F:1][C:2]1[C:3]([I:8])=[CH:4][C:5]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: Fc1ccccc1I
Solvent: CCCCCCC
Product: O=S(=O)(Cl)c1ccc(F)c(I)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoroiodobenzene (0.58 mL, 5.0 mmol) was added dropwise to chlorosulfonic acid (1.66 mL, 25 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was poured into ice and the mixture was extracted with dichloromethane (3×30 mL). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to obtain a crude residue. The crude residue was dissolved in heptane (100 mL) and the suspension was filtered. The filtrate was concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:30])[CH:26](Br)[CH2:27][CH3:28])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:26]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:30])[CH2:27][CH3:28])[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Reactant: CCC(Br)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(C(=O)OC(C)(C)C)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dry DMF (1 mL) NaH (60% dispersion mineral oil, 8 mg, 0.20 mmol) was added under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then, a solution of tert-butyl-2-bromobutyrate (0.054 mL, 0.29 mmol) in DMF (2 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(1-tert-butoxycarbonylpropyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (55 mg, 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH2:28][NH2:29]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1)=[O:9]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(Br)ccc2I)cc1OC
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-iodobenzoic acid (1-1, 500 mg, 1.529 mmol, 1.0 equiv) in dichloromethane (8 mL) was added catalytic DMF (0.012 mL, 0.153 mmol, 0.1 equiv) and oxalyl chloride (0.161 mL, 1.835 mmol, 1.2 equiv) at 0° C. The reaction mixture was stirred for 1 hour and concentrated. The crude residue was dissolved in dichloromethane (15 mL) and to the reaction was added 3,4-dimethoxybenzylamine (281 mg, 1.682 mmol, 1.2 equiv), and TEA (0.682 mL, 4.59 mmol, 3.0 equiv) at 0° C. After stirring for 10 min, the mixture was removed from the cold bath, diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 100% EtOAc in hexanes) to afford the product (1-2) as a tan solid. ESI+ MS [M+H]− C16H15BrINO3: 476.9 found, 476.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8](O)([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.S(Cl)([Cl:19])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]([Cl:19])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)(O)C(F)(F)F
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(C)(Cl)C(F)(F)F
Temperature: 40 °C

Procedure:
2-(5-Chloro-2-methoxyphenyl)-1,1,1-trifluoropropan-2-ol (C45) (1.20 g, 4.71 mmol) was treated with thionyl chloride (4 mL, 50 mmol), followed by pyridine (19.1 μL, 0.236 mmol). The reaction mixture was heated at 40° C. for 16 hours, then poured into a mixture of ice and saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (3×50 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was determined by 1H NMR to be a mixture of product and an alkene side-product derived from elimination, in a roughly 4:1 ratio; this was used in the following step without additional purification. GCMS m/z 272 (M+). 1H NMR (400 MHz, CDCl3), product peaks only: δ 2.27 (br s, 3H), 3.86 (s, 3H), 6.90 (d, J=8.8 Hz, 1H), 7.33 (dd, J=8.8, 2.5 Hz, 1H), 7.69-7.73 (m, 1H).