Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:29]([O:32][CH2:33]Br)(=[O:31])[CH3:30]>>[ClH:1].[CH3:33][O:32][C:29](=[O:31])[CH2:30][N:17]1[C:16](=[O:26])[C:15]2([CH2:27][CH2:28][N:12]([CH:2]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:13][CH2:14]2)[N:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: CC(=O)OCBr
Agent: Cl
Product: COC(=O)CN1CN(c2ccccc2)C2(CCN(C3CCCCCCCCC3)CC2)C1=O

Procedure:
The title compound, white solid, m. p. 178° C. and MS: m/e=442.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromomethyl acetate.
Reaction SMILES: [NH2:1][C@@:2]1([C:12]([OH:14])=[O:13])[C@@H:7]([F:8])[CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22].Cl>O1CCOCC1>[CH2:24]([O:23][C:21]([NH:1][C@@:2]1([C:12]([OH:14])=[O:13])[C@@H:7]([F:8])[CH2:6][C@@H:5]2[C@H:3]1[C@H:4]2[C:9]([OH:11])=[O:10])=[O:22])[CH:25]=[CH2:26]
Reactant: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of (1S,2S,3S,5R,6S)-2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (IV) (4.00 g) in dioxane (24 mL) and a saturated aqueous sodium bicarbonate solution (48 mL), allyl chloroformate (0.42 mL) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 20 hours. After addition of 1 mol/L hydrochloric acid to the reaction solution to adjust it to pH 1, the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was filtered off and then the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 6.23 g) as a colorless amorphous.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)([CH3:35])[CH2:31][S:32]2)=[CH:27][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:29]1([OH:44])[C:28]2[C:33](=[CH:34][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[S:32][CH2:31][C:30]1([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCCCCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To 9-(t-butyldimethylsilyloxy)-1-nonyne (2.23 g, 8.75 mmol) was added dry tetrahydrofuran (30 ml). Then n-butyl lithium (4.65 ml, 7.87 mol, 1.69 mol/l tetrahydrofuran solution) was added dropwise thereto at -78° C. and the resulting mixture was stirred for one hour at -20° C. At the same temperature, to the reaction solution was added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (550 mg, 1.75 mmol), as obtained in Example 26, dissolved in tetrahydrofuran (20 ml), and then the mixture was stirred for 24 hours at -10° C. When the reaction is completed, saturated ammonium chloride solution was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=9:1) to obtain 946 mg (yield: 95%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
A mixture containing 25 g of 6-methyl-5-(n-propanoyl)-2(1H)-pyridinone, 200 ml of dimethylformamide and 25 ml of dimethylformamide dimethyl acetal was heated on a steam bath for 5 and 1/2 hours and the dimethylformamide was removed by heating the reaction mixture on a rotary evaporator. The residue was refluxed with 100 ml of ethanol, the mixture cooled, and the yellow solid was collected, washed with ethanol and dried in an oven at 90°-95° C. to yield 12.8 g of 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 204°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)c(F)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Fluoro-4-hydroxy-5-methoxy-benzaldehyde (653, 1.62 g, 9.52 mmol) was dissolved in N,N-dimethylformamide (50 mL) and sodium hydride (60% dispersion in mineral oil, 530 mg, 13 mmol) was added. After 20 minutes, benzyl bromide (1.5 mL, 12 mmol) was added to the reaction mixture. The reaction was stirred at room temperature under an atmosphere of nitrogen for 5.5 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 0-50% ethyl acetate in hexane to provide compound as a white solid, consistent with the desired structure by 1H-NMR (654, 2.0 g, 81%).
Reaction SMILES: [C:1]([C@H:5]([C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[OH:8])[OH:6])([O:3][CH3:4])=[O:2].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[C@@H:5]([C:1]([O:3][CH3:4])=[O:2])[O:6]1
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)[C@@H](O)[C@H](O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1OC(c2ccccc2Cl)O[C@@H]1C(=O)OC
Yield: 60.3 %

Procedure:
In this example 50.0 g (0.28 mole) of dimethyl D-tartrate and 39.5 g (0.28 mole) of 2-chlorobenzaldehyde were refluxed for 48 hours in 500 ml of toluene in the presence of 0.2 g of p-toluenesulfonic acid. Water was azeotroped off with the aid of a Dean-Stark trap. The reaction mixture was concentrated by evaporation under reduced pressure to afford 50.8 g (60% yield) of the title compound as a solid which was washed with hexane and ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.Br[CH2:28][CH2:29][CH2:30][C:31](OCC)=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([N:26]2[CH2:28][CH2:29][CH2:30][C:31]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: CCOC(=O)CCCBr
Product: O=C1CCCN1c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reaction time: 1 h

Procedure:
3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (110 mg, 0.304 mmol) was dissolved in ethyl 4-bromobutanoate (59 mg, 0.304 mmol) before it was placed in the microwave for 60 min at 140° C. The title compound was obtained after flash chromatography. MS (ESI) m/z: Calculated: 429.1; Observed: 430.1 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH2:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>CN1C(=O)CCC1>[NH2:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:15][CH2:16]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: CSc1nc(N)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Yield: 49.8 %

Procedure:
TEA (0.243 ml, 1.74 mmol) and 6-chloro-2-(methylthio)pyrimidin-4-amine (0.309 g, 1.74 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.35 g, 1.74 mmol) in NMP (4 ml). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 90 minutes. The mixture was partitioned between water and EtOAc and washed (×2) with water. The organic phase was dried over magnesium sulphate and concentrated to give the title compound (0.294 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3.Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[C:15]3[CH2:16][CH2:17][N:18]([C:31](=[O:32])[CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)[CH2:19][CH2:20]3)[C:7]3[C:12]([CH2:13][O:14][C:4]=2[CH:3]=1)=[CH:11][CH:10]=[CH:9][N:8]=3
Reactant: O=C(O)Cc1ccncc1
Reactant: Clc1ccc2c(c1)OCc1cccnc1C2=C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCC(=C2c3ccc(Cl)cc3OCc3cccnc32)CC1

Procedure:
The title compound was prepared according to the method of Example 4 from 4-(8-chloro-5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11-ylidene)-piperidine, 4-pyridine-acetic acid hydrochloride, HOBT, EDCl and NMM in DMF. 4-(8-Chloro-5,11-dihydro[1]benz-oxepino[4,3-b]pyridin-11-ylidene)-1-(4-pyridine-acetyl)piperidine was obtained as a white foam; MS (CI, M+H)=432; anal.: found: C, 68.71; H, 5.44; N, 9.44; C25H22ClN3O2 requires: C, 69.52; H, 5.13; N, 9.73.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:33]2[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Product: COc1ccc(-c2nccc(C)c2O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1

Procedure:
By following a procedure analogous to Example 27 starting from the 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 24 and 4-methoxyphenylboronic acid, 2-(4-methoxy-phenyl)-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained and is used directly for the deacetylation step.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]1.Cl>C1COCC1>[O:2]=[CH:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]1
Reactant: COC(=O)c1cccc2ccn(CC(OC)OC)c12
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc2ccn(CC=O)c12
Temperature: 60 °C
Yield: 87.3 %

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-1H-indole-7-carboxylate (1.77 g, 6.7 mmol) from Step A above in THF (30 ml) was added 1N HCl (30 ml). The mixture was heated to 60° C. for 2 h. The solvent was evaporated and the residue purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate) to afford methyl 1-(2-oxoethyl)-1H-indole-7-carboxylate (1.27 g, 87%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.77 (s, 1H), 7.84 (dd, J=4.5, 1.0 Hz, 2H), 7.15 (t, J=8.0 Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.67 (d, J=1.5 Hz, 1H), 3.90 (s, 3H), 2.05 (s, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:25][C:26](=[O:27])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 2-bromoacetophenone (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 7 mg of white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8]C(OCC)=O)[N+:5]([O-:14])=[C:4]([NH:15]C(OCC)=O)[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[NH2:15][C:4]1[CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([NH2:8])[N+:5]=1[O-:14]
Reactant: CCOC(=O)Nc1cc(Cl)cc(NC(=O)OCC)[n+]1[O-]
Reactant: C1CCNCC1
Product: Nc1cc(N2CCCCC2)cc(N)[n+]1[O-]
Yield: 8 %

Procedure:
A mixture of 4-chloro-2,6-bis-(ethoxycarbonylamino)-pyridine 1-oxide (10.0 g., 0.03 mole) obtained according to the procedure of Example 1(a) and 60 ml. of piperidine is heated in a sealed tube at 135° C. for a period of 48 hr. The reaction mixture is concentrated to dryness and the residual material taken up in a mixture of chloroform and 10% aqueous sodium carbonate. After separating the organic and aqueous fractions, the aqueous layer is washed with chloroform, the chloroform fractions combined and dried over magnesium sulfate. The dried chloroform extract is concentrated to a volume of approximately 100 ml., cooled and filtered to afford 0.52 g., (8% yield) of 2,6-diamino-4-(1-piperidinyl)pyridine 1-oxide, m.p. 249°-265° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:24]([O:26]C)=O)=O.Cl.NC.[BH3-][C:32]#[N:33].[Na+]>CO>[CH3:32][N:33]1[C:24](=[O:26])[C:4]2[C:3](=[C:12]([O:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=2)[CH2:1]1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(C)C2
Yield: 49.8 %

Procedure:
A sealed tube was charged with a solution of dimethyl 4-formyl-5-(4-(methylsulfonyl)phenoxy)-isophthalate (210 mg, 0.535 mmol) in MeOH and aminomethane hydrochloride (72.3 mg, 1.07 mmol). After stirring the reaction at room temperature for 2 hours, NaCNBH3 (84.1 mg, 1.34 mmol) was added. The mixture was then stirred at 65° C. for 14 hours. The solvent was evaporated and replaced with ethyl acetate. The organic layer was then washed with brine (3×), dried over MgSO4, and concentrated. The crude sample was introduced into a silica gel column chromatography and eluted with 5-10% MeOH/CHCl3 to provide the desired product (100 mg, 50% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.09 (s, 3 H) 3.21 (s, 3 H) 3.94 (s, 3 H) 4.36 (s, 2 H) 7.07-7.21 (m, 2 H) 7.84 (d, J=1.13 Hz, 1 H) 7.90-8.03 (m, 2 H) 8.37 (d, J=1.13 Hz, 1 H); LC-MS (ESI)+ m/z=376.00 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([O:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([O:25]C(C)(C)C)=[O:24].[OH-].[Na+].O>COCCO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([O:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: CC(C)Oc1c(C(=O)OC(C)(C)C)n(C)c2ccc(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: CC(C)Oc1c(C(=O)O)n(C)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A suspension of 1,1-dimethylethyl 1-methyl-3(1-methylethoxy)-5-(phenylmethoxy)-1H-indole-2-carboxylate (5.6 g, 14 mmol) in 80 mL of 2-methoxyethanol is treated with a solution of 50% aqueous sodium hydroxide (5.0 g, 63 mmol) followed by the addition of 15 mL of water. The mixture is stirred at reflux for 3 hours, then cooled and added to 700 mL of water. The mixture is heated on a hot plate until nearly one phase and filtered hot. The warm filtrate is immediately treated with 50 mL of 4.0N HCl. After cooling to room temperature, followed by 1 hour in an ice bath, the precipitated solid is filtered and washed with 25% methanol in water to give 4.2 g (88%) of product suitable for further synthesis. A sample recrystallized from ethyl acetate-hexane has mp 136° C.-dec.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[C:28]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][CH3:26])[CH2:21][CH2:20]3)[C:15]2=[O:27])=[C:11]([Cl:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:31][C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[C:28]([Cl:30])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([O:25][CH3:26])[CH2:21][CH2:20]2)[C:15]1=[O:27]
Reactant: [H][H]
Reactant: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1

Procedure:
Stir (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-methoxy-cyclohexyl)-pyrrolidin-2-one (2.59 g, 5.61 mmol) and palladium hydroxide (20% on carbon) (0.300 g, 10% by weight) in 100 ml of ethyl acetate. Bubble hydrogen gas through the solution while stirring at room temperature for 5 minutes. Stir the mixture under the hydrogen gas atmosphere for 5 hours. Filter through Celite® and concentrate under vacuum to recover 2.08 g of the title compound (99%). MS (m/z): 372 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C@H:16]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]3)[CH:11]=[N:12][CH:13]=2)[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH:18]1[CH2:19][CH2:20][C@H:16](/[CH:15]=[CH:14]/[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([O:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](/C=C/c2cncc(OC3CCOCC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=C/[C@H]1CCNC1)\c1cncc(OC2CCOCC2)c1
Yield: 60.6 %

Procedure:
A solution of tert-butyl(R)-(E)-3-(2-(5-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl)vinyl)pyrrolidine-1-carboxylate (18 g, 48.13 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was stirred at ambient temperature for 2 h. The reaction was concentrated on a rotary evaporator, and the residue was partitioned between saturated sodium chloride (50 mL) and chloroform (100 mL). The mixture was basified to pH 9 with 10% aqueous sodium hydroxide solution. The organic layer was separated and the aqueous layer extracted with chloroform (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated on a rotary evaporator to give (R)-3-((E)-2-(pyrrolidin-3-yl)vinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine (8.0 g) as a gum. This was dissolved in methanol (100 mL) and galactaric acid (3.0 g, 14.6 mmol) was added and the mixture was heated to reflux. This hot solution was filtered, and filtrate was allowed to cool to ambient temperature. The crystallized product was filtered and solid was suspended in 10% water in ethanol (180 mL). The suspension was heated to reflux and hot solution was filtered. The filtrate was allowed to cool to ambient temperature. Crystallized product was filtered and dried on high vacuum pump to give (R)-3-((E)-2-pyrrolidin-3-ylvinyl)-5-(tetrahydro-2H-pyran-4-yloxy)pyridine hemigalactarate (4.5 g). MP: 179° C. 1H-NMR (CD3OD, 300 MHz): δ 8.04 (s, 1 H), 8.01 (d, J=2.2 Hz, 1 H), 7.36 (s, 1 H), 6.46 (d, J=16.0 Hz, 1 H), 6.21 (dd, J=16.0, 7.5 Hz, 1 H), 4.65-4.4.54 (m, 1 H), 4.12 (s, 1 H), 3.89-3.83 (m, 2 H), 4.80 (s, 1 H), 3.56-3.33 (m, 4 H), 3.27-3.18 (m, 1 H), 3.12-2.96 (m, 2 H), 2.23-2.14 (m, 1 H), 1.98-1.91 (m, 2 H), 1.88-1.78 (m, 1 H), 1.68-1.58 (m, 2 H); MS (m/z): 275 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12]2[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=2)[CH:5]=[C:4]([CH3:19])[N:3]=1.[N:20](OCCC(C)C)=O.[H+].[B-](F)(F)(F)F>C(O)C.[Pd]>[F:18][C:15]1[CH:14]=[N:13][C:12]([N:11]2[C:6]3[CH:5]=[C:4]([CH3:19])[N:3]=[CH:2][C:7]=3[N:8]=[N:20]2)=[N:17][CH:16]=1
Reactant: Cc1cc(Nc2ncc(F)cn2)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)CCON=O
Agent: [Pd]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: Cc1cc2c(cn1)nnn2-c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 10 h
Yield: 40.9 %

Procedure:
To a slurry of N-(2-chloro-6-methyl-3-nitropyridin-4-yl)-5-fluoropyrimidin-2-amine (13 g, 45.8 mmol) in ethanol (300 mL) was added 10% Pd/C (100 mg). The reaction was stirred for 10 h under a hydrogen atmosphere after which time the reaction was filtered and the filtrate was concentrated. The residue was diluted with ethanol (200 mL) and cooled to 0° C. Isoamyl nitrite (4.0 g, 34.0 mmol) and HBF4 (5.5 g, 34.0 mmol) were added and the reaction was stirred for 30 min at 0° C. followed by rt for 10 h. Evaporation of the solvents followed by recrystallization afforded the product as a white solid (3.2 g, 48%). MS (ESI) mass calcd. C10H7FN6, 230.07. m/z found, 231.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 9.17 (s, 2H), 8.14 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O>[Pd].C(O)(C)C>[CH3:10][C:9]1[C:2]([OH:1])=[C:3]([CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)c(C)c1O
Yield: 72 %

Procedure:
A solution of 2,4-dihydroxy-3-methylbenzaldehyde (30.0 g, 197 mmol) with isopropanol (3 L) was ice-cooled in a 5 L 3-neck flask fitted with a magnetic stirrer. Phosphoric acid (4 mL) and 10% palladium on carbon were added and the solution was sparged with nitrogen, then hydrogen. When uptake was judged to be complete (c. 1.5 hour) the solution was again sparged with nitrogen and then filtered through Celite®. The solvent was stripped off, the residue taken up in ethyl acetate, and the resulting solution washed with water (4×100 mL). The water washes were back-extracted with ethyl acetate and the combined organic layers dried over sodium sulfate and stripped down. Sublimation (95°, 0.05 torr) afforded a colorless solid (19.6 g, 72%). M.p. 107-8° C. (Lit.