Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[CH2:15]([NH2:27])[CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]([Cl:14])=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:4]([NH:27][CH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=1)=[O:5]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)C(=C(Cl)Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(=C(Cl)Cl)c2ccc(Cl)cc2)cc1OC
Temperature: 22.5 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A solution of 10.8 g (0.04 mol) of the acyl chloride prepared in Example 5 in 20 ml of methylene chloride was added dropwise to a solution of 7.24 g (0.04 mol) of homoveratrylamine and 4.04 g 25 (0.04 mol) of triethylamine in 80 ml of methylene chloride. The solution was stirred for 3 hours at 20 to 25° C., and washed with 3 N sodium hydroxide solution and then with 10% by weight strength hydrochloric acid. The organic phase was freed from solvent, and 13.85 g of the title compound were obtained from the residue following chromatography on silica gel with cyclohehane [sic]/MtBE (3:1).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 4-fluoro-3-nitro-benzoic acid methyl ester (10 g, 50.2 mmol), K2CO3 (7 g, 50.2 mmol) and 1-methyl-piperazine (11.2 mL, 100.4 mmol, 2 eq.) in 200 mL of N,N-dimethylformamide was stirred at 100° C. for 1 h. The solvent was then evaporated, the residue taken-up with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH 9:1 as eluant, affording 14 g of the title compound as orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]=[CH:4][N:3]=1.[NH3:13]>C(O)(C)C>[N:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:13])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: N
Reactant: Clc1cc(-n2cccn2)ncn1
Solvent: CC(C)O
Product: Nc1cc(-n2cccn2)ncn1
Reaction time: 96 h
Yield: 98.4 %

Procedure:
A solution of 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (1.31 g, 7.25 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 24 h. The reaction was stored at room temperature for 4 days. The solid precipitate was filtered and dried to give 6-(1H-pyrazol-1-yl)pyrimidin-4-amine (1.15 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, dd, J=2.52, 0.50 Hz), 8.30 (1H, d, J=0.76 Hz), 7.82 (1H, d, J=1.01 Hz), 7.19 (2H, br. s.), 6.88 (1H, d, J=1.01 Hz), 6.55 (1H, dd, J=2.64, 1.64 Hz). LCMS: RT=0.52 min, MH+=162.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([NH:19][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
50 g (34.5 mL, 14.3 mmol) 3,4-difluoronitrobenzene and 44.6 mL (408.6 mmol) benzylamine were combined with 600 mL acetonitrile, and then 82.3 mL (471.5 mmol) N,N-diisopropylethylamine (DIPEA) was added thereto. The resultant mixture was slowly heated to reflux. The reaction substantially completed after refluxing 5 hours, as monitored by a real-time thin layer chromatography (TLC). Then, heating was stopped and the mixture was allowed to cool to room temperature, resulting in the precipitation of a colorless transparent crystal. The mixture was filtered when substantially no more crystal precipitated. The filtrate was evaporated in a rotatory evaporator to afford a yellowish solid, which was recrystallized with ethanol to obtain a yellow crystal. Then, the yellow crystal was dried and weighed 72.5 g, with a yield of 93.7%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:41])([CH3:40])[C@@H:11]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]([CH3:30])([CH3:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])(=[O:7])=[O:6].[N-:42]=[N+:43]=[N-:44].[Na+]>CS(C)=O>[N:42]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:41])([CH3:40])[C@@H:11]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18](=[O:31])[C:19]([CH3:30])([CH3:29])[CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:13])(=[O:7])=[O:6])=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(COCc1ccccc1)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COCc1ccccc1)C(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]
Yield: 27.2 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, [2,2-dimethyl-3-(phenylmethoxy)propanoyloxy]ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (46a) (0.47 g, 0.77 mmol, max.) dissolved in 4 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 90 mg (1.4 mmol) of sodium azide (NaN3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and n-heptane (Hptn) (EtOAc/Hptn=1:4) as eluent to provide a mixture of 0.13 g (27% yield) of the title compound (46b). Rf=0.17 (EtOAc/Hept=1:4). MS (ESI) m/z 642.20 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[N:21][CH:22]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([NH2:35])=[O:34])[CH2:29][CH2:28]1>C(O)CCC>[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][C:8]([N:27]4[CH2:32][CH2:31][CH:30]([C:33]([NH2:35])=[O:34])[CH2:29][CH2:28]4)=[C:3]([C:1]#[N:2])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[CH:18][CH:19]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1ccc(Nc2nccc(-c3ccc(F)c(C#N)c3)n2)cn1
Reactant: NC(=O)C1CCNCC1
Solvent: CCCCO
Product: CC(=O)Nc1ccc(Nc2nccc(-c3ccc(N4CCC(C(N)=O)CC4)c(C#N)c3)n2)cn1
Yield: 29 %

Procedure:
A stirred solution of N-{5-[4-(3-Cyano-4-fluoro-phenyl)-pyrimidin-2-ylamino]-pyridin-2-yl}-acetamide (100 mg, 0.28 mmol) and piperidine-4-carboxylic acid amide in n-butanol (5 mL) was heated to 115° C. in a sealed tube for 48 h. The solvent was evaporated to obtain the crude compound. The crude compound was purified by preparative-HPLC to obtain the desired product as pale yellow powder (38 mg, 29%); LC-MS, Rt,=2.96 min (Method C), m/z 457 (MH+). In addition to this procedure similar reactions may also be accomplished at 110° for 16-120 h. Purification may be by preparative-HPLC or flash column chromatography.
Reaction SMILES: [C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@H:13](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][C@H:11]2[CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:39][NH2:40]>CO>[C:1]1([CH3:38])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C@@H:13]3[CH2:12][C@H:11]2[CH2:26][N:40]3[CH3:39])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CN
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2C[C@@H]3C[C@H]2CN3C)cc1
Temperature: 90 °C
Yield: 90 %

Procedure:
A Parr bottle was charged with 115 g (198.4 mmol) of (2S, 4R)-1-(4-toluenesulfonyl)-2-(p-toluenesulfonyl- oxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine and 690 ml of methanol and the bottle was then tared. Methylamine gas was bubbled through the methanol solution until 62 g (2 mol) of the gas has dissolved. The bottle was then sealed and heated to 90° C. After heating for 16 hours the reaction was cooled and the solvent was evaporated at reduced pressure. The residual solids were then partitioned between 500 ml of methylene chloride and 400 ml of 10% aqueous sodium hydroxide solution. The layers were separated and the organic layer was washed with 400 additional ml of 10% aqueous sodium hydroxide solution, and then dried over sodium sulfate. Evaporation of the solvent under reduced pressure provided 47.5 g of the desired product which represents a 90% yield. M.P.=87°-88° C.
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1.[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([S:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([CH3:16])[C:11]=2[CH3:15])[N:6]=1
Reactant: Cc1c(Cl)nc2nc(N)ccc2c1C
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Sc2ccccc2)nc2nc(N)ccc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
13 g of a 30% strength methanolic sodium methylate solution is introduced into 5.0 g (24 mmol) of 2-amino-7-chloro-5,6-dimethyl-1,8-naphthyridine and 8.0 g (72 mmol) of thiophenol in 100 ml of anhydrous methanol. The mixture is boiled under reflux for 3 hours and stirred overnight at room temperature. 200 ml of water is added, the mixture is stirred for 1 hour, and the precipitated solid is filtered off, washed with a small amount of methanol and dried under reduced pressure. There is obtained 4.7 g of a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][CH:17]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:16]([F:15])=[CH:17][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)cc3)nc2n(CC)c1=O
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.31 g (13.9 mmol) of 4-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 2.00 g (yield 51%) of Compound 146 as colorless columns.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[CH2:12][C:11]1=[O:20].C([OH:23])C.[OH-].[Na+].Cl>O>[CH3:19][C:15]1[CH:16]=[CH:17][C:18]([NH:10][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[Cl:9])=[C:13]([CH2:12][C:11]([OH:20])=[O:23])[CH:14]=1
Reactant: CCO
Reactant: Cc1cc(Cl)c(N2C(=O)Cc3cc(C)ccc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)c(Nc2ccc(C)cc2CC(=O)O)c(Cl)c1
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 g of N-(2′,6′-dichloro-4′-methylphenyl)-5-methyloxindole, 18 ml of ethanol and 1 ml of water is heated to reflux. 1.9 g of a 30% sodium hydroxide solution is slowly added and reflux is continued for 4-5 h. The solution is cooled to about 40° C. and treated slowly with a solution of 1.5 g of concentrated hydrochloric acid in 12 ml of water up to a pH of 3-4. The obtained suspension is cooled to 20° C. The crystals are collected by filtration, washed with water and dried giving 5-Methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][N:32]=1)[C:26]([O:28]C)=[O:27])=[O:9])=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:1][N:2]([CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][O:41][CH2:42][CH2:43]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:13][C:12]=1[C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][N:32]=1)[C:26]([OH:28])=[O:27])=[O:9])=[O:4]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Reaction time: 1 h
Yield: 124.2 %

Procedure:
A solution of 231 mg of methyl 2-(2-(3-(methyl(2-morpholinoethyl)carbamoyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate in 9 mL of 2:1 dioxane/water was treated with 33 mg of lithium hydroxide hydrate. After stirring for 1 h the solvent was evaporated and the residue was partitioned between dichloromethane and 3 N hydrochloric acid. The aqueous phase was evaporated to give the product as 280 mg of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:30]=1)=[O:25]>CC(O)C>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][NH:23][C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][N:34]=[C:14]([C:11]2[C:12]([OH:13])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[S:9][CH:10]=2)[CH3:16])=[O:32])=[CH:29][CH:30]=1)=[O:25]
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccco2)s1
Reactant: CC(=O)c1csc(-c2ccc(Br)cc2)c1O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccco2)s1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 25 °C
Yield: 72 %

Procedure:
2-(4-Bromophenyl)-3-hydroxy-4-methylcarbonylthiophene (50.1 mg, 0.17 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid (furan-2-ylmethyl)amide (45.0 mg, 0.17 mmol) prepared in Reference Synthetic Example 13 in 2-propanol (4.0 mL) were heated with p-tosylic acid monohydrate (6 mg) at 100° C. for 7.5 hours and cooled to room temperature. The precipitated solid was recovered by filtration, washed with 2-propanol (1 mL) and dried to give the desired product (yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.[CH2:13](I)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:11])[CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: CCC(=O)Cc1ccc(OC)cc1

Procedure:
Educts: 4-methoxyphenyl acetic acid chloride (70); ethyl iodide
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(O)C>O.[OH-].[Na+]>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:3]2[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=2[OH:1])=[CH:12][CH:11]=1
Reactant: O=c1ccocc1O
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1ccoc(C(O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[4-Fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one: With stirring at room temperature, 5.6 g of pyromeconic acid (3-hydroxy-pyran-4-one) [CAS No.: 496-63-9] are dissolved in 10 ml of water and 24.5 ml of 2N NaOH. 6.33 g of 4-fluorobenzaldehyde and 25 ml of ethanol are added and the reaction mixture is stirred at room temperature for 18 hours. For working-up, the ethanol is removed using a rotary evaporator and the aqueous solution that remains is neutralised with 24.5 ml of 2N HCl. The product that has crystallised out is filtered off, washed with water and dried, yielding 2-[(4-fluorophenyl)-hydroxy-methyl]-3-hydroxy-pyran-4-one in the form of colourless crystals. M.p.: 154°-156° C.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:7][CH3:8].[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([CH:29]=[O:30])=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[C:11]([O:10][C:6](=[O:9])[CH:7]([CH3:8])[CH:29]([C:19]1[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[OH:30])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCC(=O)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C(=O)OC(C)(C)C)C(O)c1ccc(Cl)nc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A first intermediate compound, 7-Chloro-3-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: Diisopropyl amine (freshly distilled over sodium, 12.8 mL, 91.4 mmol, 2.2 equiv.) was dissolved in Et2O (40 mL) and cooled to −78° C. Butyl lithium (2.5 M solution in hexane, 37.0 mL, 91.4 mmol, 2.2 equiv.) was added slowly under nitrogen atmosphere. The mixture was stirred for 15 min and t-butyl propionate (13.8 mL, 91.4 mmol, 2.2 equiv.) was added as a solution in dry THF (20 mL). The reaction mixture was stirred for 30 min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (10.0 g, 42.0 mmol, 1.0 equiv.) was added as a solution in a minimum amount of dry THF (35 mL). A bright yellow precipitate was formed within 10 min and stirring became difficult. The reaction was allowed to warm up to RT. The reaction mixture turned dark red and was poured into saturated NH4Cl (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. 3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester was obtained as a yellow thick syrup which upon drying under high vacuum became a foamy solid (20.0 g, crude). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.3 h
Yield: 76 %

Procedure:
A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.25 g, 12.0 mmol), in anhydrous THF (10 ml) was added portionwise to a slurry of sodium hydride (60% dispersion in oil, 0.63 g, 13.8 mmol) in THF (35 ml) and the mixture stirred for 0.3 h at 0° C. A solution of benzyl bromide (2.37 g, 13.8 mmol) in dry THF (2 ml) was added and the mixture warmed to room temperature and stirred for 18 h. Water (70 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (100:0→97:3) to give the desired product (2.53 g, 76%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2), 3.42-3.50 (4H, m, 2 of CH2), 4.10-4.16 (1H, m, CH--OBn), 4.53 (2H, s, OCH2Ar), 7.26-7.39 (5H, m, Ar).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:14](N(CC)CC)C.N[C@@H](C(O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S([O-])(=O)=O.[Mg+2].C(=O)C1C=CC=CC=1.Cl.C(N(CC)CC)C>>[CH3:14][O:12][C:11](=[O:13])[C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[N:2]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.0 eq D-phenylalanine HCl (1.6 g, 7.4 mmol) was added 1.0 eq triethylamine to dissolve the D-phenylalanine. To this solution was added 1 equiv. of MgSO4 followed by the addition of 1.0 eq benzaldehyde, the reaction was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was stripped of solvent and pumped on the residue contained a good deal of triethylamine hydrochloride which was removed by dissolving the product in THF and filtering out the TEA.HCl. The crude benzylidene looked fine by NMR and was all taken on in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:42]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 100 mg, 0.193 mmol), 3-(methanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3)4 (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60° C. overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).