Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:22][CH2:23][N:24]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[C:10]([CH3:11])[CH:9]=4)=[O:8])[CH2:25][CH2:26]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)cnc1F
Yield: 52.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-5-methylnicotinic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.4 g) described in Preparation Example 96, the title compound (1.2 g) was obtained.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH3:22])\[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH2:22][Cl:27])\[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H](O/N=C(\C(=O)O)C(=O)CCl)CC1

Procedure:
tert-Butyl (Z)-2-(trans -4-acetoxycyclohexyloxyimino)3-oxobutyrate (327 mg, 1 mmol) was reacted with sulphuryl chloride (0.8 ml) in glacial acetic acid (2 ml) by an analogous procedure to that described in Example 57d to give the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:6]=[C:5]2[CH3:11]
Reactant: ClCCN1CCCC1
Reactant: Cc1n[nH]c2ccc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(CCN2CCCC2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
A solution of 5-bromo-3-methyl-1H-indazole (4.23 g, 20.0 mmol) in DMSO (150 mL) was treated with Cs2CO3 (19.55 g, 60.00 mmol) and 1-(2-chloroethyl)pyrrolidine hydrochloride (5.27 g, 31.0 mmol). After stirring for 16 hours at room temperature, the mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, MeOH/EtOAc/hexanes, 1.4:5) gave the title compound (0.67 g, 11%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J=1.5 Hz, 1H), 7.42 (dd, J=9.0, 1.5 Hz, 1H), 7.26 (d, J=9.0, 1H, overlapping with solvent peak), 4.43 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.58-2.55 (m, 4H), 2.53 (s, 3H), 1.79-1.74 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[N:6].Br.Br.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: N#CCCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 80 %

Procedure:
A mixture of 11.5 parts of 4-chlorobutanenitrile, 48.5 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of N,N-dimethylformamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinebutanenitrile; mp. 130.5° C. (intermediate 94).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.[Li]CCCC>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([B:24]([OH:25])[OH:23])=[CH:18][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)ccc2Cl)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution of 2-(5-bromo-2-chlorophenoxy)-5-(trifluoromethyl)pyridine (2.6 g, 7.3 mmol) and triisopropylborate (2.0 mL, 8.76 mmol) in toluene (15 mL) and THF (7 mL) under a N2 atmosphere was added n-BuLi (6.8 mL, 10.95 mmol) while maintaining the reaction at −70° C. The reaction was stirred for 1 h at −40° C. Gradually the temperature was increased to −20° C. and then 0° C. The reaction was quenched with 2N HCl and allowed to warm to RT. The reaction mixture was concentrated and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (2.8 g). 1H NMR (500 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.29 (m, 3H), 7.94 (s, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.36 (d, J=8.05 Hz, 2H); m/z (316.4, M− H−).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: O=C1Nc2cccc(F)c2C1=CO
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Product: O=C1Nc2cccc(F)c2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 62.6 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (600 mg, 1.2 equiv.) and 4-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (407 mg, 2.27 mmol, 1 equiv.) (4-Fluorooxindole may be prepared as described in Synthesis 1991, 10, 871) are reacted to give the named compound as a yellow solid (542 mg, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([OH:45])[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([CH:34]2[CH2:43][CH:42]([OH:44])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:45][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:40]=3)[O:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cccc(F)c2)O3)nc1

Procedure:
2-(3-Fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 890 mg of 2-(3-fluorophenyl)chroman-4,6-diol (Example 9(b)). The product was purified by column chromatography using gradient elution with ethyl acetate-heptane (20%→33%) and then crystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1, 2.9 Hz), 7.48 (m, 1H), 7.35-7.31 (m, 2H), 7.26-7.19 (m, 3H), 7.02 (dd, 1H, J 8.8, 2.9 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.67 (d, 1H, J 6.4 Hz), 5.34 (d, 1H, J 10.4 Hz), 4.98 (m, 1H), 2.36 (m, 1H), 1.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:13][C:14]2[C:19]([C:20]3[CH:25]=[C:24]([NH:26][CH3:27])[N:23]=[CH:22][N:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:8]1[C:9]2[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([NH:13][C:14]3[C:19]([C:20]4[CH:25]=[C:24]([NH:26][CH3:27])[N:23]=[CH:22][N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)[C:4]=2[CH:5]=[CH:6][N:7]=1
Reactant: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Reactant: O=P(Cl)(Cl)Cl
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Cl)nccc23)ncn1
Temperature: 120 °C

Procedure:
6-Methyl-5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-ylamino)isoquinolin-1(2H)-one (195 mg, 0.54 mmol) was suspended in POCl3 (10 mL) and heated at 120° C. for 3 h. POCl3 was removed in vacuo and the residue was washed with toluene three times. The residue was added to water and the resulting solid collected by filtration, washing with saturated aqueous sodium bicarbonate and water. The resulting title compound was dried in vacuo. MS (M+H)+ 377.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C@:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Yield: 81.2 %

Procedure:
A mixture of the enantiomer (R)-(−)-5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (3.8 g, 13.3 mmol) and 10% palladium on carbon (48% water wet, 270 g) in methanol (90 ml) was hydrogenated for 1 hour at 50 psi of hydrogen. The catalyst was filtered off through a pad of celite and the solvent was evaporated under reduced pressure; the residue was purified by flash chromatography (eluting with ammoniated chloroform/methanol, 95:5 to 85:15), provided the title compound (2.5 g, 10.8 mmol, 81%): electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.CN(C=O)C>CCOC(C)=O>[CH3:17][O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=2)[CH2:20]1
Reactant: COC1CCNC1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CCN(c2nc(C(F)(F)F)ccc2C=CC(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
To a suspension of 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (50 mg, 0.198 mmol) in 3-methoxy-pyrrolidine (40 mg, 0.396 mmol) was added DMF (1.0 ml). The mixture was stirred for 12 hours at room temperature. The reaction mixture was diluted with EtOAc and then washed two times with 1N-HCl and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was chromatographed to yield the 3-[2-(3-methoxy-pyrrolidin-1-yl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid (59 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.F[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][C:36]([F:39])([F:38])[F:37]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:29]4[CH:30]=[CH:31][CH:26]=[C:27]([O:35][C:36]([F:37])([F:38])[F:39])[CH:28]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1ccc(F)c(OC(F)(F)F)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(OC(F)(F)F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 13.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-fluoro-3-(trifluoromethoxy)phenylboronic acid (20 mg, 0.106 mmol). The mixture was heated at 120° C. under microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(3-(trifluoromethoxy)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.32 mg, 14%). 1H-NMR (MeOD): 2.23 (m, 2H), 3.10 (s, 3H), 5.80 (d, 1H), 6.98 (m, 1H), 7.13 (m, 1H), 7.26 (m, 2H), 7.34 (m, 3H), 7.38 (m, 3H), 7.46 (m, 2H).
Reaction SMILES: CO.[C:3]([OH:13])(=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]>[Rh].C(O)(=O)C>[CH:6]1([CH:4]([OH:5])[C:3]([OH:13])=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)C(O)c1ccccc1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C(O)C1CCCCC1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 200 mL methanol were added 38.0 g mandelic-acid, 2.5 mL acetic acid, and 7.5 g rhodium on carbon (5%, Engelhard 5864). The mixture was sealed in an autoclave, purged with nitrogen, and then filled with hydrogen gas. Hydrogenation was carried out at room temperature for 8 hours at 1400 psi hydrogen. The reaction mixture was then removed from the autoclave and filtered. The filtrate was concentrated and recrystallized from toluene. The colorless crystals were collected by filtration and dried under vacuum to give 31.8 g (80.5%) of racemic 2-cyclohexyl-2-hydroxyacetic acid. 1H NMR (DMSO-d6): δ (ppm) 3.71 (d, 1H), 1.66-1.55 (m, 6H), 1.16-1.09 (m, 5H). 13C NMR (DMSO-d6): δ (ppm) 175.27, 74.19, 41.15, 28.86, 26.74, 25.84, 25.76, 25.57. IR (KBr): ν (cm−1) 3440, 2933, 2856, 1718, 1450, 1280, 1255, 1230, 1103. Anal. Calcd. for C8H14O3: C, 60.74; H, 8.92. Found: C, 61.12; H, 9.28. mp 135-136° C.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([NH2:7])=[N:3]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.CC([O-])(C)C.[K+].O>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:7][C:4]2[N:5]=[N:6][N:2]([CH3:1])[N:3]=2)=[N:10][CH:11]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Cn1nnc(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(Nc2ccc(Br)cn2)n1
Yield: 1.5 %

Procedure:
2-methyl-2H-tetrazole-5-amine (7.7 g, 78 mmol), 2-chloro-5-bromopyridine (10 g, 52 mmol), and potassium tert-butylate (11.6 g, 104 mmol) were dissolved in 100 mL THF, heated under reflux and reacted for 12 h. Water was added, extracted with ethyl acetate, and the organic phase was dried, concentrated, and the solid was separated by a silica gel column (dichloromethane:methanol=100:1) to obtain 5-bromo-N-(2-methyl-2H-tetrazol-5-yl)pyridine-2-amine 200 mg, at a yield of 1.5%.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([O:11][C:12](=[O:21])[CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4]2.[CH:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:40][C:39]1[CH:38]=[N+:37]([O-:41])[CH:36]=[C:35]([Cl:42])[C:34]=1[CH2:33][CH:32]([O:31][C:29]([C:27]1[S:28][C:24]([CH2:22][NH:20][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:21])[O:11][C@@H:5]2[CH:6]3[CH2:7][CH2:8][N:3]([CH2:10][CH2:9]3)[CH2:4]2)=[CH:25][CH:26]=1)=[O:30])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)ccc1OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of [(3R)-quinuclidin-3-yl]2-amino-2-phenylacetate bis hydrochloride salt (273 mg, 0.82 mmol) in ethanol (10 mL) was added the single enantiomer 2 of [2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)ethyl] 5-formylthiophene-2-carboxylate (Intermediate 75, 135 mg, 0.27 mmol) and acetic acid (40 μL, 0.68 mmol). The resulting mixture was stirred at room temperature for 16 h. Sodium cyanoborohydride (45 mg, 0.68 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (3 mL) and ethyl acetate (3 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×3 mL). The aqueous phase was basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (2×3 mL). The combined organic fractions were extracted with 1 M aqueous hydrochloric acid (2 mL). Brine (2 mL) was added and the aqueous layer was extracted with chloroform (5 mL and 2 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (2 mL), passed through a hydrophobic frit and the solvent was removed by evaporation under reduced pressure. Purification by preparative HPLC gave the title compound as an off-white solid (50 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][CH:25]([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:24]([N:23]([CH3:22])[C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: CNCC(C)C
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added N-methylisobutylamine (0.15 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (108 mg, 44% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H31Cl N2 O2, 378.9, found, 379.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 1:1 mixture of rotomers, δ 7.47-7.45 (m, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.30 (m, 1H), 3.71 (s, 2H), 3.20-3.02 (m, 3H), 2.92 & 2.90 (2 s, 3H total), 2.80-2.70 (m, 2H), 2.60-2.50 (m, 6H), 1.95-1.80 (m, 1H), 1.78-1.70 (m, 4H), 0.76-0.58 (m, 6H); 100 MHz 13C NMR (CDCl3) 1:1 mixture of rotomers, line list δ 176.6, 175.8, 146.4, 135.2, 135.1, 134.0, 130.9, 130.8, 126.4, 123.7, 123.6, 73.5, 73.3, 57.9, 56.7, 55.6, 54.3, 41.4, 41.0, 36.1, 35.0, 29.0, 28.2, 27.9, 26.9, 23.7, 20.2, 20.1.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][N:2]1C(OC(C)(C)C)=O>C(O)(C(F)(F)F)=O.ClCCl>[CH2:3]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9]2)[CH2:1][NH:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Benzyl 2-tert-butyl 2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (33.4 g, 92.8 mmol) was dissolved in a solution of TFA (50 mL) and dichloromethane (200 mL) and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was neutralized with saturated aqueous Na2CO3 (100 mL). The aqueous solution was washed with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated to give a yellow oil, which upon co-evaporation with dichloromethane provided benzyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (SM-2a) as a white solid. (17.6 g, 73%). MS (ES+) 261.4 (M+H)+. 1H NMR (CDCl3) δ 1.67-1.89 (m, 4H), 2.86-3.18 (m, 2H), 3.40-3.64 (m, 7H), 5.12 (s, 2H), 7.30-7.39 (m, 5H).
Reaction SMILES: [CH:1]([C@H:4]1[C:20](=[O:21])[O:19][C@H:18]([CH:22]=[CH2:23])[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:28])([CH3:27])[C:6](=[O:29])[NH:5]1)([CH3:3])[CH3:2].[Br:30][CH2:31][CH2:32]C=C>ClCCCl>[Br:30][CH2:31][CH2:32]/[CH:23]=[CH:22]/[C@@H:18]1[CH2:17][C:16](=[O:24])[NH:15][CH2:14][C:13]2=[N:25][C:10](=[CH:11][S:12]2)[C:9](=[O:26])[NH:8][C:7]([CH3:27])([CH3:28])[C:6](=[O:29])[NH:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:20](=[O:21])[O:19]1
Reactant: C=CCCBr
Reactant: C=C[C@@H]1CC(=O)NCc2nc(cs2)C(=O)NC(C)(C)C(=O)N[C@@H](C(C)C)C(=O)O1
Solvent: ClCCCl
Product: CC(C)[C@@H]1NC(=O)C(C)(C)NC(=O)c2csc(n2)CNC(=O)C[C@@H](/C=C/CCBr)OC1=O
Temperature: 85 °C

Procedure:
To a mixture of (7S,10S)-7-isopropyl-4,4-dimethyl-10-vinyl-9-oxa-16-thia-3,6,13,18-tetraazabicyclo[13.2.1]octadeca-1(17),15(18)-diene-2,5,8,12-tetraone (20 mg, 0.047 mmole) in 2 mL 1,2-dichloroethane was added 4-bromo-1-butene (25.6 mg, 0.19 mmole) and Zhan-1 catalyst (3.2 mg, 0.0047 mmole). The mixture was briefly degassed and then heated in a sealed tube at 85° C. overnight. The crude product was concentrated and passed through a silica gel plug to get a mixture of the desired product and recovered starting material (2:1 ratio). It was further purified by reversed phase chromatography, eluted with 0-80% water/CH3CN to get the desired product (8 mg, 32% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=[O:26]>CCCCCCC.CCOC(C)=O>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:25]([N:15]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][C:17]([F:18])([F:20])[F:19])=[O:26]
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from (2-methoxy-[3,4]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 3-fluoro-5-(trifluoromethyl)benzoic acid (CAS RN 161622-05-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow solid (16%). MS (ESI): m/z=474.104 [M+H]+.