Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3(C=O)[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([C:22]3([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)[O:13][N:12]=2)=[CH:9][CH:10]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCOc1ccc(-c2noc(C3(C=O)CC3)c2-c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(-c2noc(C3(CN4CCN(C)CC4)CC3)c2-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a mixture consisting of 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]cyclopropanecarbaldehyde (this example, Step A, 0.490 g) in dichloromethane (15 mL) is added 1-methyl-piperazine (0.173 mL) and sodium triacetoxyborohydride (0.420 g.) The mixture is stirred for two hours. Another portion of 1-methyl-piperazine (0.08 mL) and sodium triacetoxyborohydride (0.18 g) are added to the mixture and the mixture is stirred overnight. The mixture is treated with water and is extracted with dichloromethane. The organic layer is separated and is dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography to afford 1-{1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl}-4-methyl-piperazine (0.500 g.)
Reaction SMILES: [CH2:1]([C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][CH:28]=1)[O:15][CH:16]([C:22](=O)[CH2:23][CH3:24])[C:17](OCC)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35]>C(O)C>[NH2:36][C:34]1[N:35]=[C:17]([OH:18])[C:16]([O:15][C:14]2[CH:26]=[CH:27][CH:28]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:13]=2)=[C:22]([CH2:23][CH3:24])[N:33]=1
Reactant: CCCCCCCCCCCc1cccc(OC(C(=O)CC)C(=O)OCC)c1
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: CCCCCCCCCCCc1cccc(Oc2c(O)nc(N)nc2CC)c1
Yield: 15.7 %

Procedure:
A stirred solution of 8.9 grams (0.028 mole) of ethyl 2-(3-undecylphenoxy)-3-oxopentanoate and 2.5 grams (0.028 mole) of guanidine carbonate in 30 mL of ethanol was heated at reflux for about 6 hours. The reaction mixture was then concentrated under reduced pressure to a residue. The residue was taken up in 50 mL of water and 5 mL of acetic acid, and the mixture was extracted with 50 mL of diethyl ether. The ether layer was extracted with 20 grams of aqueous 10% sodium hydroxide and then with 100 mL of water. The water extract was made acidic with acetic acid, and then it was extracted with 50 mL of diethyl ether. The ether extract was concentrated under reduced pressure to a residue. The residue was then taken up in 25 mL of heptane, and the mixture was again concentrated under reduced pressure to a residual solid. The solid was slurried in an additional 25 mL of heptane, and then it was collected by filtration. The solid was dried under reduced pressure, yielding 1.7 grams of 2-amino-6-ethyl-4-hydroxy-5-(3-undecylphenoxy) pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](Br)=[CH:29][C:28]=4[CH3:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:36](/B(O)O)=[CH:37]/[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:32]=[CH:31][C:30](/[CH:36]=[CH:37]\[CH3:38])=[CH:29][C:28]=4[CH3:34])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:35])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: C/C=C\B(O)O
Reactant: Cc1cc(Br)ccc1OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1ccc(OC(=O)N2CCC(Oc3ccn(-c4ccc(S(C)(=O)=O)cc4)c(=O)c3)CC2)c(C)c1
Temperature: 100 °C
Yield: 71.9 %

Procedure:
A mixture of 4-bromo-2-methylphenyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (32.5 mg, 0.058 mmol, Example 143), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4.76 mg, 5.79 μmol, Combiphos Catalysts, Inc.), (Z)-prop-1-enylboronic acid (14.92 mg, 0.174 mmol, Aldrich) and cesium carbonate (94 mg, 0.289 mmol, Aldrich) in DMF (0.6 mL) and water (0.12 mL) was heated under microwave conditions (100° C., 20 min) The reaction mixture was purified by preparative HPLC (C18 column; 40-100% methanol in water containing 0.05% trifluoroacetic acid) to give the title compound (21.8 mg, yellow solid, 72%) upon lyophilization. MS (ESI) 523 (M+H).
Reaction SMILES: N1C=CC(C2[C:8](C3C=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)=[N:9][NH:10]C=2)=CC=1.[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44](=O)[CH2:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[C:45]([C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)=[CH:8][NH:9][N:10]=2)=[C:40]([F:53])[CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Reactant: c1ccc2nc(COc3ccc(-c4n[nH]cc4-c4ccncc4)cc3)ccc2c1
Product: Fc1cc(OCc2ccccc2)ccc1-c1n[nH]cc1-c1ccncc1

Procedure:
Following the procedure for the preparation of 2-[4-(4-Pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin-4-yl-ethanone provided the title compound. MS: (M+H m/z=346.3).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C.[CH2:14]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[S:20])[CH2:15][CH2:16][CH3:17]>CO>[ClH:1].[CH3:12][C:11]1[C:2]([S:20][C:19](=[N:18][CH2:14][CH2:15][CH2:16][CH3:17])[NH:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2nc1Cl
Reactant: CCCCNC(=S)NCCCC
Agent: C
Solvent: CO
Product: CCCCN=C(NCCCC)Sc1nc2ccccc2nc1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-methylquinoxaline (3.572 g., 0.02 mole) was dissolved in 50 ml. of methanol, treated with Norit and filtered. The filtrate was added to 3.767 g. (0.02 mole) of 1,3-dibutylthiourea dissolved in 25 ml. of methanol. The resulting solution was stirred at room temperature for 1 hour and evaporated on a rotary evaporator. The residual oil was triturated successively with several portions of ether, 2:1 pentane-ether and acetone, and was filtered and washed with pentane, to give 2.60 g. (38.6%) of product as a tan solid, m.p. 97°-99°.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][N@@:11]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[Si:1]([O:8][CH2:9][C@@H:10]([NH:11][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:12][O:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC1CO[Si](C)(C)C(C)(C)C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccccc1)CO[Si](C)(C)C(C)(C)C
Yield: 29.9 %

Procedure:
(S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)aziridine-1-carboxylate (5.0 g, 17.4 mmol), phenol (4.92 g, 52.3 mmol), K2CO3 (24 g, 174 mmol) and 150 mL of acetonenitrile were mixed, and heated to reflux for 48 h. The mixture was filtrated, and the filtrate was concentrated in vacuo. The residue was dissolved in 100 mL of EA, which was washed with water (50 mL×2), brine (50 mL) and dried with Na2SO4. The solution was concentrated in vacuo to give crude product, which was purified with flash column to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-phenoxypropan-2-ylcarbamate (2.0 g, 5.2 mmol, yield 30%) 1H NMR (CDCl3, 400 MHz) δ 0.0 (s, 6H), 0.87 (s, 9H), 1.45 (s, 9H), 3.71 (dd, 1H), 3.85 (dd, 1H), 3.98 (d, 2H), 4.05 (s, 1H), 6.93 (m, 3H), 7.28 (m, 2H). MS ESI +ve m/z 382 (M+1).
Reaction SMILES: [CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18](Br)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1.Cl.[F:29][C:30]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31]1>>[CH:1]1([C:4]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([N:32]3[CH2:33][CH2:34][C:30]([F:35])([F:29])[CH2:31]3)=[CH:17][N:16]=2)=[O:14])([C:6]2[N:10]=[C:9]([CH3:11])[O:8][N:7]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: FC1(F)CCNC1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(Br)cn2)C2CC2)no1
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(N3CCC(F)(F)C3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 78h, using 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid [1-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (Example 78g) and 3,3-difluoropyrrolidine hydrochloride (CAN 163457-23-6) as starting materials and isolated (17 mg, 32%) as a white solid; MS (ESI, m/z): 476.4 (M+H+).
Reaction SMILES: C(=O)C1C=CC=CC=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].C([N:33](C(C)C)CC)(C)C.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=[CH:22][C:23]=2[S:26]([NH2:33])(=[O:28])=[O:27])[CH2:13][CH2:12]1
Reactant: NCC1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=Cc1ccccc1
Product: NCC1CCN(c2cc([N+](=O)[O-])ccc2S(N)(=O)=O)CC1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of benzaldehyde (20.3 mL, 200 mmol) and 4-aminomethylpiperidine (22.8 g, 200 mmol) in 250 mL toluene was heated at reflux until 3.6 mL of H2O was collected in a Dean-Stark trap. To the cooled reaction mixture was added 4-nitrobenzenesulfonyl chloride (44.3 g, 200 mmol) and diisopropylethyl amine (34.8 mL, 200 mmol) and stirring was continued for 1 hour. The intermediate imine was decomposed by the addition of 200 mL of 1N KHSO4 solution. The solids formed were filtered, washed sequentially with water and ether. The collected solids were dried to provide 65 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1>>[F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)=[O:8]
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: NCC1CCCCN1
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In still another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. Hydroquinone is contacted with 2,2,2-trifluoroethyl trifluoromethanesulfonate under conditions to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of the 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced using hypochlorite to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. Subsequently, the 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Finally, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpiperidine, whereby there is formed 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Si:27]([O:1][CH2:2][C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
To a solution of (S)-tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.00 g, 4.60 mmol) in DCM (10 ml) were added sequentially triethylamine (1.3 ml, 9.21 mmol), tert-butylchlorodiphenylsilane (1.414 ml, 5.52 mmol) and DMAP (0.56 g, 4.60 mmol) and the resulting mixture was stirred overnight at ambient temperature. The mixture was diluted with water and the aqueous phase was extracted with DCM. The organic layer was separated and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0→50% EtOAc/hexanes) to afford the title product (1.0 g, yield: 48%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1.[Br-].[CH2:20]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH:30](=[C:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[O:16][CH2:17][CH3:18])[CH2:4][CH2:3]1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1c(NC2CCC(=O)CC2)ccnc1C
Agent: [Br-]
Product: CCCCCCCCCCC=C1CCC(Nc2ccnc(C)c2OCC)CC1
Yield: 51 %

Procedure:
Preparation was carried out analogously to Example 27 from 4-(4-oxocyclohexylamino)-3-ethoxy-2-methylpyridine and undecyl triphenylphosphonium bromide. Yield: 51%
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1COCC1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part D) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4×25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96% yield) by flash chromatography on silica gel eluting with EtOAc(100-95%)/Et3N(0-5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.C(OC([N:28]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][C:29]21[CH2:32][CH2:31][CH2:30]2)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:30]1[C:29]2([CH2:33][CH:34]([NH:37][C:2]3[N:7]=[C:6]([C:13]4[S:9][C:10]5[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=5[CH:12]=4)[CH:5]=[CH:4][N:3]=3)[CH2:35][CH2:36][NH:28]2)[CH2:32][CH2:31]1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC12CCC2
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2sc(-c3ccnc(NC4CCNC5(CCC5)C4)n3)cc2c1

Procedure:
The racemic title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and 8-Amino-5-aza-spiro[3.5]nonane-5-carboxylic acid tert-butyl ester followed by BOC-deprotection with 4N-HCl in dioxane.
Reaction SMILES: [CH2:1]([P:10]([O:15][CH2:16][CH3:17])(=[O:14])[O:11][CH2:12][CH3:13])[P:2]([O:7][CH2:8][CH3:9])(=[O:6])[O:3][CH2:4][CH3:5].[H-].[Na+].[H][H].Br[CH2:23][C:24]1[CH:25]=[N:26][S:27][N:28]=1>O.C1(C)C=CC=CC=1>[CH2:16]([O:15][P:10]([CH:1]([P:2]([O:7][CH2:8][CH3:9])(=[O:6])[O:3][CH2:4][CH3:5])[CH2:23][C:24]1[CH:25]=[N:26][S:27][N:28]=1)(=[O:14])[O:11][CH2:12][CH3:13])[CH3:17]
Reactant: BrCc1cnsn1
Reactant: [H][H]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(Cc1cnsn1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 55 %

Procedure:
A solution of 1.62 g. tetraethyl methanediphosphonate in 10 ml. anhydrous toluene is added dropwise to 0.2 g. sodium hydride (69%) in 10 ml. anhydrous toluene. After termination of the evolution of hydrogen, 1 g. 4-bromomethyl-1,2,5-thiadiazole in 10 ml. anhydrous toluene is added thereto and the reaction mixture stirred for 12 hours at ambient temperature. A little water is then added and the organic phase is separated off, dried and evaporated. The residue is purified over a column of silica gel (100 g.; elution agent methylene chloride/methanol 98:2 v/v). There is thus obtained 1.18 g. of the desired product in the form of a colourless oil; yield 55% of theory.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)cccc1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2c(F)cccc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-6-fluoro-phenyl)-acrylic acid.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N([O-])=[O:13].[Na+].C>S(=O)(=O)(O)O.O>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([OH:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)ccc1Cl
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 78.1 %

Procedure:
5-Amino-2-chlorobenzoic acid (85%, 10 g, 49.7 mmol) was suspended in diluted sulphuric acid (1.25%, 800 mL) and cooled to 5° C. on an ice bath. Sodium nitrite (5 g, 72 mmol) dissolved in water (150 mL) was added slowly while keeping the temperature of the reaction below 5° C. After addition of the sodium nitrite the reaction was stirred for another 45 min at 5-10° C. until a clear solution was obtained. The reaction mixture was poured into hot (70-85° C.) water (1.5 L), charcoal added and the reaction mixture heated at reflux for 25 min. Filtration and extraction with ethyl acetate afforded 6.7 g of the desired product as light brown crystals.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[Cl:20][C:21]1[CH:22]=[C:23](O)[C:24]([CH3:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:16]([O:15][C:13]([NH:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:23]2[C:24]([CH3:31])=[C:25]([CH:30]=[C:21]([Cl:20])[CH:22]=2)[C:26]([O:28][CH3:29])=[O:27])[CH2:7][CH2:8]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of (cis)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (5.36 mL, 22.93 mmol), methyl 5-chloro-3-hydroxy-2-methylbenzoate (4.0 g, 19.94 mmol), and cesium carbonate (9.74 g, 29.9 mmol) was added N,N-dimethylformamide (DMF) (100 mL). The suspension was stirred at RT for 15 min, then heated at 65° C. under nitrogen septum for 3 days. The reaction was allowed to cool to RT and was poured into ice/saturated NH4Cl (500 mL). The mixture was neutralized with 1 M HCl and extracted with 1:1 EtOAc/ether (2×). The combined organics were washed with brine, dried over magnesium sulfate, and concentrated. The resultant liquid was dried under high vacuum for 2 h. Purification of the residue by flash chromatography (200 gram Isco silica column, 4-50% ether/heptane) gave methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)oxy)-5-chloro-2-methylbenzoate (1.87 g, 4.70 mmol, 23.57% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27-1.48 (m, 13 H) 1.80 (d, J=10.61Hz, 2 H) 1.98-2.07 (m, 2 H) 2.25 (s, 3 H) 3.23-3.33 (m, 1 H) 3.82 (s, 3 H) 4.30-4.45 (m, 1 H) 6.86 (d, J=7.58 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.35 (d, J=2.02 Hz, 1 H). MS(ES) [M+H]+ 420.1 (Na adduct).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:31]C1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.FC1C=C2C(B3OC(C)(C)C(C)(C)O3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C(O)=O>C(#N)C>[Cl:31][C:14]1[CH:15]=[C:16]2[C:8]([C:5]3[N:4]=[C:3]([NH:18][CH:19]([C:24]4([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][C:21]([OH:23])=[O:22])[C:2]([F:1])=[CH:7][N:6]=3)=[CH:9][NH:10][C:11]2=[N:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(F)cc34)ncc2F)CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Solvent: CC#N
Solvent: O=CO
Product: CC1(C(CC(=O)O)Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)CCCCC1

Procedure:
Compound 83 was synthesized in a manner similar to 3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoic acid, 78, using 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: 1H NMR (400 MHz, MeOD) δ 9.05 (d, J=2.1 Hz, 1H), 8.39-8.24 (m, 2H), 8.16 (d, J=4.9 Hz, 1H), 5.23 (d, J=10.4 Hz, 1H), 2.86 (d, J=15.6 Hz, 1H), 2.65 (m, 1H), 1.58 (m, 7H), 1.37 (m, 3H), 1.05 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.37 minutes (M+H) 442.36.