Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[Br:13]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:13][C:8]1[C:7]2[C:11](=[CH:12][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(Br)n[nH]c2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 6-carboxyindazole (4.0 g) in acetic acid (140 ml) was added bromine (1.53 ml), and the mixture was stirred in the dark for 24 hours. After the addition of saturated sodium bisulfite (50 ml) and brine (100 ml), the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting solid was powdered and vacuum dried to afford 3-bromo-6-carboxyindazole as a light brown solid (5.88 g, 99%), mp >250°.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>O1CCCC1>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1nc(C(O)CN)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C(O)CNC(=O)Cc2ccc(O)cc2)cs1
Reaction time: 8 h

Procedure:
3.16 g (20 mmol) of 2-Hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine are dissolved in 80 ml of absolute tetrahydrofuran and, successively, 3.84 g (20 mmol) of 4-hydroxy-phenylacetic acid, 6.3 g (24 mmol) of triphenylphosphine, 5.6 ml (40 mmol) of triethylamine and 2 ml (20 mmol) of carbon tetrachloride are added. After stirring overnight, the mixture is concentrated, the residue is taken up in 2N hydrochloric acid and the solution is extracted three times with methylene chloride. The aqueous phase is then adjusted to pH 7 with 2N sodium hydroxide solution and evaporated to dryness. The residue from evaporation is extracted by boiling several times with a mixture of chloroform/methanol (1:1). The extracts are concentrated, and the residue is purified on a silica gel column using ethyl acetate/methanol=50:1 as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCOc1ccc(-c2cc(CCl)ccn2)cc1
Product: CCOc1ccc(-c2cc(CN(c3ccc(OC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-ethoxyphenyl)pyridine (248 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1>>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][O:21][CH:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: ClCc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2ccc3c(c2)OCCO3)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate with 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxin [Brit. Pat. 566732 (1943)] there was obtained tert-butyl (3RS,4RS)-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethoxy)-4-(4-fluorophenyl)-piperidine-1-carboxylate as a colourless solid; MS: 444 (M+H)+ ;
Reaction SMILES: C([NH:8][C@H:9]([C:27]([O:29][CH3:30])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH3:30][O:29][C:27](=[O:28])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])=[CH:15][CH:16]=1)[NH2:8]
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1

Procedure:
N-Boc-4-(2-nitrophenoxy)-(L)-phenylalanine, methyl ester (600 mg) was stirred in a solution of 1N hydrochloric acid in ethyl acetate (10 mL) for 18 hours at room temperature. A precipitate formed, the solvent was removed by rotoevaporation, and co-evaporated with Et2O (2×). The solid was than suspended with ethyl acetate, filtered, washed with diethyl ether, and allowed to air dry. The title compound was recovered (490 mg) and used in the subsequent reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH:33]3[CH3:32])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1COCCN1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CCOCC1C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (960 mg, 2.076 mmol; Example 210, Step A) in 1,2-dichloroethane (15 mL) was added 3-methylmorpholine (Enamine Ltd, Kiev, Ukraine) (0.471 mL, 4.15 mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol). After stirring overnight, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was extracted with dichloromethane (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 1 to 10% methanol/dichloromethane) to afford the title compound as the major diastereomer. Stereochemistry of the 3-morpholine stereocenter is unknown.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[F:13][C:14]1[C:15]([F:21])=[C:16](O)[CH:17]=[CH:18][CH:19]=1>CN(C=O)C>[CH:3]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[C:15]=2[F:21])[CH2:5][CH2:4]1
Reactant: OCCCCCCC1CC1
Reactant: Oc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(OCCCCCCC2CC2)c1F
Yield: 99.3 %

Procedure:
3.9 g of NaH (60% in oil) and 20 g of 6-cyclopropyl-hexanol were added to a solution of 8.5 g of difluoro-phenol in 100 ml of DMF. After a reaction time of 24 hours at room temperature, the solution was poured onto ice and extracted with CH2Cl2. After drying (Na2SO4) and removal of the solvent by distillation, 16.5 g of 6-cyclopropylhexyloxy-2,3-difluorobenzene were obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][O:12][CH3:13])[N:7]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCc1nc2c(Cl)cccc2[nH]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: COCc1nc2c(Cl)cccc2n1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 90.3 %

Procedure:
[step 3] Using 4-chloro-2-(methoxymethyl)-1H-benzo[d]imidazole (50 mg, 0.25 mmol) obtained in step 2 and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (96 mg, 0.27 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (107 mg, 89%) was obtained.
Reaction SMILES: C([NH:8][C@H:9]([C:24]([N:26]([CH3:35])[C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.Cl.CCOC(C)=O.[C:43]1([CH:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:50](Cl)=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@@H:9]([C:24]([N:26]([CH3:35])[C@@H:27]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])=[O:25])[NH:8][C:50](=[O:51])[CH:49]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: C[C@H](c1ccccc1)N(C)C(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](c1ccccc1)N(C)C(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1
Yield: 29.9 %

Procedure:
Prepared according to the method described in Examples 2(b) and 2(c) above from (R)-N2 -(Boc)-N5 -(Cbz)-N-methyl-(S)-N-(1-phenylethyl)-ornithine amide (5.3 g; 11 mmol; from step (a) above), EtOAc (75 mL), then HCl/EtOAc (75 mL), 2.5 hours reaction time for the deprotection, then CH2Cl2 (50 mL), diphenylacetyl chloride (2.6 g; 11 mmol) followed by pyridine (3.0 mL; 37 mmol; instead of DiPEA) over 1 min, overnight reaction time, diluted with CH2Cl2 (100 mL) for the work-up procedure. The crude material was purified by chromatography on silica gel with EtOAc:hexane (1:1) to provide 1.9 g (30%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18](O)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:31][C:32]1[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=1[NH2:38].CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]2[NH:31][C:32]3[C:33](=[O:41])[N:34]([CH2:39][CH3:40])[CH:35]=[CH:36][C:37]=3[N:38]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1ccc(N)c(N)c1=O
Reactant: O=C(NC1CCCC(C(=O)O)C1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCn1ccc2nc(C3CCCC(NC(=O)OCc4ccccc4)C3)[nH]c2c1=O
Temperature: 0 °C
Yield: 88 %

Procedure:
In a 100 mL round bottom flask, 3-benzyloxycarbonylamino-cyclohexanecarboxylic acid (0.53 g, 1.96 mmol), TEA (0.44 g, 4.31 mmol), and HOBt (0.53 g, 3.92 mmol) were added sequentially to a solution of 3,4-diamino-1-ethyl-1H-pyridin-2-one (0.30 g, 1.96 mmol) in DMF (15 mL) at room temperature. The solution was then cooled to 0° C., EDCI (0.75 g, 3.92 mmol) was added, and the reaction mixture was allowed to stir, with warming to room temperature. After stirring for 17 h, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried with MgSO4, and concentrated. The solid was rinsed with Et2O to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.68 g, 84% yield). The intermediate amide (0.43 g, 1.04 mmol) was dissolved in glacial acetic acid (6.26 g, 104.2 mmol) and heated at 120° C. for 2 days. After cooling to room temperature, the solvent was removed in vacuo and the crude product was purified by flash chromatography eluting with 3% MeOH in CH2Cl2 to give [3-(5-ethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.22 g, 54% yield). 1H-NMR (DMSO): δ 7.35 (m, 6H), 6.53 (m, 1H), 5.01 (s, 2H), 3.99 (m, 2H), 3.43 (m, 1H), 2.86 (m, 1H), 2.07 (m, 1H), 1.83 (m, 3H), 1.42 (m, 3H), 1.20 (m, 3H), 1.17 (m, 1H). MS: calculated for C22H26N4O3+H 395.2; found: 395.4.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:27])[CH:21]=[CH:22][CH2:23][N:24](C)[CH3:25])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CNC1C=CC=CC=1>>[I:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:27])[CH:21]=[CH:22][CH2:23][NH:24][CH3:25])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC=CC(=O)Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1
Solvent: CNc1ccccc1
Product: CNCC=CC(=O)Nc1ccc2ncnc(Nc3cccc(I)c3)c2c1

Procedure:
N-{4-[(3-iodophenyl)amino]quinazoline-6-yl}-4-(methylamino)-2-butenamide was prepared as described above in Compound 5, using methylaniline instead of dimethylamine in step (ii).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[NH2:1][C:2]1[C:3]([NH2:9])=[CH:4][CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])[N:7]=1
Reactant: Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2F)nc1N
Temperature: 105 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 6-amino-2-bromo-5-nitropyridine (2.0 g, 9.2 mmol) and 2-fluorophenylboronic acid (2.57 g, 18 mmol) in dimethoxyethane (60 mL) were added 2M aqueous sodium carbonate solution (18 mL) and tetrakistriphenylphosphine palladium(0) (106 mg, 0.092 mmol). The mixture was stirred at 105° C. for 16 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate (30 mL) and methanol (30 mL). To the solution was added 10% palladium carbon (200 mg), and the mixture was stirred at room temperature for 14 hours under a hydrogen atmosphere. After removal of the palladium catalyst by filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give the title compound (1.87 g, 100%) as a reddish brown oil.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Ca+2:11]>O>[C:1]([O:9][OH:10])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Ca+2:11].[Ca+2:11].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[OH:10][O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [O-2]
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)OO

Procedure:
A large batch of dicalciumhydroxy malate was produced by mixing 19.16 kg of malic acid in 68.19 L of water. In a separate tank, 16.33 kg of calcium oxide was mixed in 68.19 L of water. The two solutions were slowly mixed together and stirred. A milky solution containing the product resulted, which was spray dried to obtain a powdered product of dicalciumhydroxy malate.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][C:23]2[C:31]3[C:26](=[C:27]([C:32]4[N:36]=[C:35]([C:37]5[CH:42]=[CH:41][C:40]([O:43][CH:44]([CH3:46])[CH3:45])=[C:39]([Cl:47])[CH:38]=5)[O:34][N:33]=4)[CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:48])[CH:24]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:47][C:39]1[CH:38]=[C:37]([C:35]2[O:34][N:33]=[C:32]([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]4[C:26]=3[N:25]([CH3:48])[CH:24]=[C:23]4[CH2:22][CH2:21][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:36]=2)[CH:42]=[CH:41][C:40]=1[O:43][CH:44]([CH3:45])[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 136.4 %

Procedure:
To a stirred solution of ethyl hydroxyacetate (23 mg) in DMF (5 mL) was added NaH (18 mg). The reaction mixture was stirred at 20° C. for 15 mins. Then a solution of 2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl 4-methylbenzenesulfonate (D127) (25 mg) in DMF was added dropwise. The mixture was stirred at room temperature for 24 h. The reaction was quenched with water, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, 2 M hydrochloric acid and brine, dried over sodium sulphate and evaporated to give the crude product ethyl ({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}oxy)acetate (D104) (30 mg), used directly in the next step. MS (ES): C26H28ClN3O5 requires 497; found 498.2 (M+H+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][C:12]=2[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: C1CCNCC1
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCCCC3)cc2N2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.67 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 5.0 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 3.3 g of the title compound as oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:15][CH2:14][N:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12](=[O:24])[CH:11]=1>C(O)(=O)C>[I:1][C:11]1[C:12](=[O:24])[N:13]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][O:15][C:10]=1[CH3:9]
Reactant: CCOC(=O)C(C)(C)N1COC(C)=CC1=O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)N1COC(C)=C(I)C1=O
Temperature: 42.5 °C
Reaction time: 5 h
Yield: 21.5 %

Procedure:
N-Iodosuccinimide (238 g) was added to a stirred solution of ethyl 2-(2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (200 g) in acetic acid. The mixture was stirred at 40-45° C. for 5 hours then at ambient temperature overnight and evaporated. The residue was diluted with ether, washed with water, sodium carbonate solution (2M) and brine, dried (MgSO4) and evaporated. A solution of the residue in ethanol was cooled to -40° C. to give ethyl 2-(2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl)-2-methylpropanoate (66.9 g), m.p. 85-87° C.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:11][C:12]=3[CH:13]=2)[NH:4][C:3]1=[O:22].[CH3:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([N:24]([CH3:23])[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][O:15][C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]4[NH:4][C:3](=[O:22])[N:2]([CH3:1])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CNC1CCCCCC1
Reactant: Cn1c(=O)[nH]c2nc3ccc(OCCCC(=O)O)cc3cc21
Product: CN(C(=O)CCCOc1ccc2nc3[nH]c(=O)n(C)c3cc2c1)C1CCCCCC1

Procedure:
This compound, m.p. 234.5°-236.5° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-1-methyl-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoic acid and N-methylcycloheptylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:2]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c[nH]c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1c[nH]c2ccccc12
Temperature: -40 °C

Procedure:
Compound 29 (1.8 g, 5.44 mmol) was transferred to a flame-dried flask filled with argon and dissolved in anhydrous THF then cooled to −40° C. Triethylamine (0.72 g, 7.07 mmol) was added by syringe followed by MeSO2Cl (0.75 g, 6.53 mmol). The temperature of the reaction mixture was allowed to rise to room temperature (10–15 minutes) before it was quickly filtrated and concentrated. The crude oil was dissolved in CH2Cl2 and washed with H2O. The organic phase was dried with MgSO4, filtrated and concentrated in vacuo to a dark, brown oil. The crude product was used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH2:30][O:31]S(C)(=O)=O)[CH:18]=3)[O:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl.[CH:39]1([CH2:42]O)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][O:31][CH2:30][C:19]2[CH:18]=[C:17]([C:15]3[O:14][N:13]=[C:12]([C:10]4[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=4)[N:16]=3)[CH:22]=[CH:21][C:20]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:41][CH2:40]1
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COS(C)(=O)=O)c3)n2)cc1F
Reactant: OCC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)cc1COCC1CC1
Temperature: 130 °C

Procedure:
Methyl 2-fluoro-4-[5-(2′-methyl-2-{[(methylsulfonyl)oxy]methyl}biphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzoate, prepared as in example 58, step 1, (75 mg; 0.15 mmol) was dissolved in cyclopropylmethanol (5 mL). The solution was then heated in the microwave at 130° C. for 10 min. Sodium hydroxide (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was heated at 60° C. for 10 min in the microwave. Hydrogen chloride (151.05 μL; 5 M; 0.76 mmol) was added and the mixture was evaporated to dryness. The crude was purified with MD Autoprep, to afford the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) 13.63 (br s, 1H), 8.35 (d, J=1.5 Hz, 1H), 8.18 (dd, J=7.8, 1.9 Hz, 1H), 8.13-8.08 (m, 1H), 8.04 (dd, J=8.0, 1.4 Hz, 1H), 7.96 (dd, J=11.1, 1.2 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.15 (d, J=7.2 Hz, 1H), 4.30-4.20 (m, 2H), 3.20-3.17 (m, 2H), 2.04 (s, 3H), 1-0.91 (m, 1H), 0.46-40 (m, 2H), 0.14-0.09 (m, 2H). LC/MS (Method B): 457.3 (M−H)−, 459.2 (M+H)+. HPLC (Method A) Rt 5.67 min (Purity: 98.5%).