Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])=[CH:17][CH:16]=3)=[CH:13][CH:12]=[C:11]2[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:6]([CH3:34])[CH:5]=1)(=[O:3])[NH2:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])=[CH:19][CH:20]=3)=[CH:13][CH:12]=[C:11]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:6]([CH3:34])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N3CCOC3=O)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(N2CCOC2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
To a solution of ethyl 3-(1-(4-carbamoyl-2-methylphenyl)-5-(4-(2-oxooxazolidin-3-yl)phenyl)-1H-pyrrol-2-yl)propanoate (67 mg, 0.15 mmol) in THF/H2O (1 mL, v/v=1/1) was added lithium hydroxide monohydrate (7 mg, 0.15 mmol). The mixture was stirred at room temperature for 6 h. THF was evaporated in vacuo. The residue was acidified to pH=5 with 5% hydrochloric acid, concentrated and purified by prep-TLC to afford the titled compound as a brown solid (24 mg, yield 39%).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:28][CH3:29])[C:17]3[C:22]([C:23]=2[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH3:27])[CH:18]=3)=[CH:11][CH:10]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:24]([C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:26][CH3:27])=[CH:20][CH:21]=2)[N:16]([CH2:28][CH3:29])[C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:30])=[O:5])=[CH:10][CH:11]=1)#[N:25]
Reactant: CCn1c(-c2ccc(OCC(=O)OC(C)(C)C)cc2)c(C#N)c2ccc(OC)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2ccc(OCC(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Yield: 98.9 %

Procedure:
[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) was stirred in 20% TFA in CH2Cl2 at room temperature for 3 hours. This was concentrated and the residue was partitioned between H2O and EtOAc. The organic layer was dried and concentrated. The residue was triturated with CH2Cl2 to yield [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:14][CH:13]([CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:17]4)[C:12](=[O:29])[C:8]=3[NH:9][C:10]=2[CH:11]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:14][CH:13]([CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:17]4)[C:12](=[O:29])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc2c3c([nH]c2c1)C(=O)C(CC1CCN(Cc2ccccc2)CC1)C3
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1c2[nH]c3cc(O)ccc3c2CC1CC1CCN(Cc2ccccc2)CC1
Temperature: 110 °C
Yield: 52.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-6-methoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]cyclopent[b]indol-3-one (200 mg, 0.51 mmol) and 48% HBr (30 ml) was heated to 110° C. for 3.5 hours. The reaction mixture was allowed to cool and saturated sodium bicarbonate was added until pH 8. The mixture obtained was filtered and the aqueous filrate was extracted with ethanol and the resulting mixture was filtered. Aqueous Na2S2O4 was added to the ethanolic filtrate and the light brown solution obtained was concentrated. The residue was partitioned between water and boiling ethyl acetate. The organic layer was combined and washed with water, brine, dried, filtered and concentrated. The residue was purified through silica gel column chromatography to give the title compound as a yellow solid (100 mg). The material was recrystallized from ethanol to give a pale yellow solid, mp. 250°-252° C.; Anal. Calc. for C24H26N2O2.0.25H2O: C, 76.06; H, 7.05; N, 7.39; ound: C, 76.27; H, 6.67; N, 7.36.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C.O>C(#N)C>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: OCCCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OCCCCCSc1nc2ccccc2[nH]1
Yield: 75 %

Procedure:
1.5 g of 2-mercaptobenzimidazole and 1.7 g of 5-bromopentanol were refluxed for 5 hours in an acetonitrile solvent containing 1.2 g of triethylamine. The reaction mixture was cooled, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 1.77 g of the title compound (yield: 75%).
Reaction SMILES: C(O[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:10]1[CH:11]=[C:12]2[CH:13]=[CH:14][C:15]([OH:19])=[C:16]([C:16]3[C:17]4[C:12](=[CH:11][CH:10]=[CH:9][CH:18]=4)[CH:13]=[CH:14][C:15]=3[OH:19])[C:17]2=[CH:18][CH:9]=1
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-benzyloxy-2-naphthol (50 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3g, Yield 80%. [α]D25=−157.4 (c=0.3 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.89 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.80 (d, J=8.7 Hz, 2H, 2×HC (4)), 7.24 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.10–7.22 (m, 12H, 2×HC (6), 10×PhH), 6.50 (d, J=2.1 Hz, 2H, 2×HC (8)), 5.01 (s, 2H, 2×OH), 4.73.4.84 (m, 4H, 4×OCH2). e.e. 95%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>ClCCl>[C:38]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[N:9]=1)(=[O:41])[CH:39]=[CH2:40]
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
To a solution of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (0.626 mmol, 250 mg) in dichloromethane (25 ml) at 0° C. was added triethylamine (0.626 mmol, 0.087 ml, 63.3 mg) and, drop wise, acryloyl chloride (0.657 mmol, 0.053 ml, 59.5 mg). The resulting mixture was stirred at 0° C. for 2 hours. The mixture was washed with water, dried over magnesium sulfate. After evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 126 mg of (S)-4-(3-(1-acryloylpyrrolidin-2-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (44.4% yield). Data: UPLC (C) Rt: 1.50 min; m/z 454.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:36]([O:39][CH2:40][CH2:41]Br)(=[O:38])[CH3:37]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]([S:23]([C:26]4[CH:27]=[CH:28][CH:29]=[C:30]5[C:35]=4[N:34]=[CH:33][CH:32]=[CH:31]5)(=[O:25])=[O:24])[CH2:37][C:36]([O:39][CH2:40][CH3:41])=[O:38])=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(COc2ccc(C#N)cc2)nc2cc(NS(=O)(=O)c3cccc4cccnc34)ccc12
Reactant: CC(=O)OCCBr
Product: CCOC(=O)CN(c1ccc2c(C)cc(COc3ccc(C#N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12

Procedure:
Prepared analogously to Example 1d from 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-(quinoline-8-sulphonylamino)-quinoline and bromoethyl acetate.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]1[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:11]=[CH:12][C:13]=1[C:14]([O:16]C)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC(C)([O-])C.[Na+].CN(C)C=O.O>C(OCC)(=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:10]2[C:9]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][NH:1][C:14](=[O:16])[C:13]=3[CH:12]=[CH:11]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(=CN)c1c(C(=O)OC)ccn1Cc1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Reaction time: 0.42 h
Yield: 537.9 %

Procedure:
A mixture of methyl 2-{2-amino-1-[(ethyloxy)carbonyl]ethenyl}-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrole-3-carboxylate (2.95 g), sodium tert-butoxide (0.38 g) and dimethylformamide (20 ml) was irradiated with microwaves at 180° C. for 2.5 h. The procedure was repeated five times, the cooled solutions combined, added slowly to iced water then stirred for 25 minutes. A precipitate formed which was dissolved in ethyl acetate and washed with water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown solid (14.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:26])[CH:9]([CH2:13][CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:15][CH2:14][CH2:13][CH:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:26])[C:10]([OH:12])=[O:11]
Reactant: CN(C(=O)OC(C)(C)C)C(CCN1C(=O)c2ccccc2C1=O)C(=O)O
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C(CCN)C(=O)O

Procedure:
11.8 g (32.6 mmol) of the compound from example 5A was dissolved in approx. 640 ml ethanol and 23.8 ml (488 mmol) hydrazine hydrate was added to the reaction mixture. After stirring over night, the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The raw product was dissolved in ethanol and approx. 50 g silica gel was added, the solvent was removed under reduced pressure. The resulting solid was added onto a approx. 500 g silica gel column and chromatographed. Solvents used were dichloromethane/methanol 9/1 to dichloromethane/methanol 1/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 2.98 g (12.8 mmol, 39% of theory) product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>C(#N)C.O>[F:1][C:2]1[C:7]([N+:16]([O-:17])=[O:15])=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1O
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)c([N+](=O)[O-])c1O
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to −30° C. to −40° C. and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO2 (5% ethyl acetate in hexanes) gave 0.58 g of the title product as bright yellow solid (68% yield).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:20])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[NH2:22]O>C(O)C>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:20][N:22]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=2)=[CH:11][CH:12]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 65.3 %

Procedure:
A mixture of ethyl 2,4-dioxo-4-(4-(trifluoromethyl)phenyl)butanoate (6.89 g, 23.9 mmol) and hydroxylamine hydrochloride (2.0 g, 28.7 mmol) in ethanol (120 mL) was stirred at reflux overnight. The volatiles were removed in vacuo, and the residue purified by silica gel chromatography, eluting with dichloromethane to obtain the title compound (4.5 g, 15.6 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1c[nH]c2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(1 H-indol-3-yl)-1-hexanone were reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(1H-indol-3-yl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2Br)=[N:15][NH:16][CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(O)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[S:19][CH:20]=[CH:21][C:22]=3[N:16]([CH3:17])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNN=C(c1sccc1Br)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cu]I
Agent: COC(C)O
Product: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-[(3-Bromo-thiophen-2-yl)-(methyl-hydrazono)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (700 mg, 1.74 mmol) was mixed with CuI (20 mg), CsCO3 (650 mg, 1.15 eq) in methoxyethanol (10 mL). The mixture was heated to 70° C. for 2 hr. then stirred overnight at room temperature. The solvent was stripped on rotary evaporator. The residue was extracted into EtOAc then washed with brine and concentrated down to an oil. This oil was purified via chromatography (eluted with 0-10% MeOH in DCM) yielding 520 mg (68%) of the desired product.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@H:12]([CH3:14])[C@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@H:11]12
Reactant: COc1ccc(CN2C[C@H](C)[C@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CNC[C@H]2NC(=O)O[C@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7S,7aR)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7S,7aR)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]C=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH:22]1C2C(=CC=CC=2)C(C(Cl)=O)=N1>>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][NH:10][C:11]([C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][N:22]=3)=[O:12])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: O=C(NCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1n[nH]c2ccccc12
Product: O=C(NCC12CCN(CC1)CC2)c1n[nH]c2ccccc12

Procedure:
N-((quinuclidin-4-yl)methyl)-1H-indazole-3-carboxamide was prepared in a similar manner to N-((quinuclidin-4-yl)methyl)-1H-indole-3-carboxamide, substituting 1H-indazole-3-carbonyl chloride as the electrophile. 1HNMR: 13.6 (bs, 1H); 9.65 (bs, 1H); 8.45 (t, 1H); 8.15 (d, 1H); 7.62 (d, 1H); 7.41 (t, 1H); 7.2 (t, 1H); 3.28 (m, 2H); 3.21 (m, 6H); 1.70 (m, 6H). MS (m/e): 285.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CO>[CH3:12][N:13]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CNCCc1ccccn1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)Cc1cccc([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
6.8 g of 3-nitrobenzyl chloride in 25 ml of methanol are slowly added dropwise to a solution of 5.4 g of 2-(2-methylaminoethyl)pyridine in 20 ml of methanol at 40° C. 15 ml of triethylamine in 15 ml of methanol are subsequently added, and the mixture is stirred for 15 hours at 40° C. After removal of the solvent by evaporation in vacuo, the residue is taken up in 300 ml of water and extracted three times with dichloromethane. After drying over sodium sulphate, the dichloromethane is evaporated in vacuo and the residue is chromatographed on silica gel (eluent: dichloromethane/methanol 100:5).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.C([O-])(=O)C.[Na+]>[Pd].CO>[CH2:10]([C:4]1[C:5]([F:9])=[CH:6][N:7]=[CH:2][N:3]=1)[CH3:11]
Reactant: CCc1nc(Cl)nc(Cl)c1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncncc1F
Reaction time: 5 h
Yield: 34 %

Procedure:
A mixture of 2,4-dichloro-6-ethyl-5-fluoropyrimidine (10 g) (see Preparation 7(iii)), sodium acetate (8.83 g), 5% palladium-on-charcoal (50% "wet", 2 g) and methanol (30 ml) was hydrogenated at 50° C. and 3 atmospheres pressure for 5 hours. The resulting slurry was filtered carefully through a cellulose-based filter-aid, the pad was washed with further methanol (5 ml) and the resulting orange filtrate was distilled at 64° C. and atmospheric pressure to provide a colourless distillate. This was partitioned between water (300 ml) and ether (40 ml) and the two phases separated. The organic phase was washed with water (4×50 ml), dried over MgSO4 and the solvent was removed at room temperature under reduced pressure to provide the title compound as a pale yellow liquid (2.2 g).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Na+].Cl>CO>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:15][CH3:16])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2])(=[O:14])[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(=O)C(C)C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C(C)C)cc1C(=O)O
Yield: 100.5 %

Procedure:
5-Isobutyryl-2-methoxybenzoic acid methyl ester (143.1 mg, 0.60 mmol) was dissolved in methanol (5 mL). 2 N aqueous sodium hydroxide (1 ml) was added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (134 mg, yield:quantitative) as a white crystal.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(=O)=O.CS(C)=O.[C:14]([O:18][C:19](=[O:32])[N:20]([C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][CH2:30]O)[CH2:24][CH2:23]1)[CH3:21])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC.C(OC(=O)N(C)[C@H]1CC[C@H](CCC=O)CC1)(C)(C)C.[CH3:59][CH2:60][O:61][C:62]([CH2:64]P(OCC)(OCC)=O)=[O:63].C[O-].[Na+]>C(Cl)Cl.CCOCC.C(O)C>[CH2:60]([O:61][C:62](=[O:63])[CH:64]=[CH:30][CH2:29][CH2:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:20]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:32])[CH3:21])[CH2:23][CH2:24]1)[CH3:59]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCO)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCC=O)CC1
Agent: C[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C=CCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1.4 ml (16.24 mmol) oxalylchloride was added to a dry-ice cooled solution (−78° C.) of 1.78 ml (25 mmol) DMSO in 40 ml CH2Cl2. After 10 min. stirring at −78° C., 2.39 g (12.49 mmol) of trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, dissolved in 5 ml CH2Cl2, was added. 15 min later, 8.7 ml (62.4 mmol) Et3N was added and the reaction-mixture was allowed to attain RT. The mixture was diluted with Et2O and then washed with 1N HCl and water. After evaporation of the solvents, a solution of crude trans-Methyl-[4-(3-oxo-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (3.24 g, 12.02 mmol) and of 2.73 ml (13.3 mmol) triethyl phosphono acetate in 30 ml ethanol, was treated under ice-cooling with 1.37 g (24.05 mmol) NaOMe. The solution was stirred for 20 h at RT, and then concentrated in vacuo. The crude residue was dissolved in Et2O and washed with water. The organic layers were concentrated in vacuo and the crude product purified by chromatography on silica gel with EtOAc/Hexane 1:4 to yield 2.46 g (58%, 2 steps) of clean trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pent-2-enoic acid ethyl ester, MS: 339 (M).
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.F[C:22](F)(F)[B].[K].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:13]1([C:4]2[CH:5]=[C:6]([CH3:22])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[OH:2])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: [B]C(F)(F)F
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 52.1 %

Procedure:
To a microwave tube charged with 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (500 mg, 1.45 mmol), Pd(dppf)Cl2 (96 mg, 0.13 mmol), potassium trifluoro-methyl-boron (177 mg, 1.45 mmol) and cesium carbonate (1420 mg, 4.36 mmol) was added tetrahydrofuran (2.5 mL) and water (1.25 mL). The reaction heated at 110° C. for 35 min under microwave irradiation. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo to yield a brown oil. Purification by silica gel chromatography (0-6% ethyl acetate/hexanes) provided 2-cyclopentyl-4-methyl-5-nitro-phenol (167 mg, 52% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.43-7.38 (m, 1H), 7.22 (s, 1H), 3.28-3.21 (m, 1H), 2.43 (s, 3H), 1.96-1.91 (m, 2H), 1.80-1.51 (m, 6H).