Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:41])[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[NH2:40])=[N:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=1)=[O:41])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
2-[2-(3-tert-Butoxycarbonylaminopropoxy)-4-(methylthio)benzoylamino]-N-(5-chloropyridin-2-yl)-5-fluorobenzamide was prepared by methods described in Example 4-E from 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and N-(5-chloropyridin-2-yl)-2-amino-5-fluorobenzamide (1.53 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](Cl)=[O:13].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])=[O:13]
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: CCNCC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Prepared analogously to Example 4.1.d. from (2-chloro-4-nitrophenyl)acetic acid chloride and diethylamine in ethyl acetate. Yield: 3.7 g (100% of theory); C12H15ClN2O3 (M=270.71); calc.: molecular ion peak (M+H)+: 271/273; found: molecular ion peak (M+H)+: 271/273; Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pt]=O.C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COc1ccccc1N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 41.3 %

Procedure:
A mixture of 5.00 g (0.0133 m) of 1-[(p-nitrophenyl)sulfonyl]-4-(o-methoxyphenyl)piperazine, 0.28 g of platinum oxide and 150 ml of chloroform is shaken under pressure in a Parr hydrogenator. After hydrogen ceases to be taken up (1 hour), the reaction mixture is filtered through a fine sintered glass funnel. The filtrate is taken to dryness and crystallized once from methanol/methylene chloride and a second time from methanol to give 1.9 g (41%) of 1-[(p-aminophenyl)sulfonyl]-4-(o-methoxyphenyl)-piperazine of melting point 230°-232° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1>CC(O)=O.O=[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: O=C(O)Cc1cccnc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CC1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(pyridin-3-yl)acetic acid (274 mg, 2.0 mmol, 1.0 eq) in AcOH (2 mL) was added PtO2 (226 mg, 1.0 mmol, 0.5 eq). The mixture was stirred at room temperature for 16 h under H2. The catalyst was filtered out and the filtrate was concentrated to give 2-(piperidin-3-yl)acetic acid as a slight yellow solid (300 mg, Y: 81%). ESI-MS (M+H)+: 143.1. 1H NMR (400 MHz, CD3OD) δ: 3.34-3.31 (m, 1H), 2.84-2.77 (m, 1H), 2.64-2.57 (m, 3H), 2.18-2.10 (m, 3H), 1.86-1.83 (m, 2H), 1.71-1.67 (m, 1H), 1.24-1.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34](Cl)=[O:35].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[S:30][C:31]([Cl:37])=[CH:32][C:33]=1[C:34]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:35]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cc(Cl)sc5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 2,5-dichlorothiophene-3-carbonyl chloride (0.088 g, 0.41 mmol) in CH2Cl2 was added Et3N (0.086 mL, 0.62 mmol) and the mixture stirred at room temperature under nitrogen for 30 minutes. The mixture was concentrated and purified by silica gel chromatography, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a light yellow solid (0.177 g, 79%). 1H NMR (300 MHz, DMSO-d6): δ 11.80 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.27 (s, 1H), 7.05 (d, J=9.0 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.48 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.73-3.82 (m, 2H), 3.38-3.44 (m, 6H). APCI MS m/z 545 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[OH:12].NC1C=CC(O)=CC=1[F:21]>>[F:21][C:4]1[CH:5]=[C:6]([F:11])[C:7]([NH2:8])=[CH:2][C:3]=1[OH:12]
Reactant: Nc1ccc(O)cc1F
Reactant: O=[N+]([O-])c1c(F)ccc(O)c1F
Product: Nc1cc(O)c(F)cc1F
Yield: 97 %

Procedure:
This compound was prepared from 2,4-difluoro-3-nitrophenol (2.35 g, 13.4 mmol) in the manner described for 4-amino-3-fluorophenol, affording 1.89 g (97%) of 2,4-difluoro-5-aminophenol as a tan solid. 1H-NMR (DMSO-d6) δ 9.26 (s, 1H), 6.89 (t, J=10.7 Hz, 1H), 6.33 (t, J=9.2 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:25][CH2:26][CH2:27]I)=[CH:21][NH:22]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:25][CH2:26][CH2:27][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])[CH2:10][CH2:11]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: Clc1ccc2c(CCCI)c[nH]c2c1
Product: Clc1ccc2c(CCCN3CCN(c4cccc(Cl)c4Cl)CC3)c[nH]c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 6-chloro 3-(3-iodopropyl)-1H-indole. 1H NMR (CDCl3): 1.95 (t, 2H); 2.55 (t, 2H); 2.65 (b s, 4H); 2.80 (t, 2H); 3.10 (b s, 4H); 6.95–7.05 (m, 2H); 7.10 (d, 1H); 7.10–7.20 (m, 2H); 7.35 (s, 1H); 7.55 (d, 1H); 7.95 (b s, 1H). Ms m/z: 422 (MH+), 424.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18]O.[Br:20]CCCC1N=C(C2C=CC=CC=2)OC=1C>>[Br:20][CH2:18][C:17]#[C:16][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCCBr
Reactant: Cc1oc(-c2ccccc2)nc1CCCC#CCO
Product: Cc1oc(-c2ccccc2)nc1CCCC#CCBr
Yield: 80 %

Procedure:
Alcohol 1-8 (1.2 g, 4.7 mmol) was treated in a manner similar to the preparation of bromide 1-5. Chromatography with 10% EtOAc/Hexanes gave the product 1-9 as a colorless oil (1.7 g) in 80% yield. NMR CDCl3 (δ): 7.97 (2H, m); 7.40 (3H, m); 3.93 (2H, s); 2.60 (2H, m); 2.34 (3H, s); 2.28 (2H, m); 1.89 (2H, m).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of 2-bromothiophene (1.0 g, 6.14 mmol) in 1,2-dimethoxyethane (11 mL) was added 4-fluorophenylboronic acid (1.12 g, 7.99 mmol), followed by Pd(PPh3)4 (360 mg, 0.31 mmol) and a 2M Na2CO3 aq. solution (8 mL). The reaction mixture was heated at 80° C. for 4 h, then was poured onto a mixture of ice and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (MgSO4) and concentrated under reduced pressure to yield a yellow oil. The crude product was filtered through a plug of silica with the aid of hexanes to give 4-fluorophenylthiphene (1.04 g, 95%). TLC (hex) Rf=0.40.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:60]=[C:61]([Cl:63])[CH:62]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([O:46]CC2C=C(Cl)C=C(CN3CCC3)C=2)=[O:45])[CH2:25][CH2:24][CH2:23]1.[OH-].[Na+].O.CC#N>C1COCC1.CO>[N:22]1([CH2:26][C:27]2[CH:28]=[C:29]([CH:60]=[C:61]([Cl:63])[CH:62]=2)[CH2:30][N:31]2[C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:40]([CH3:43])=[N:41][N:42]=4)[C:34]=3[CH:33]=[C:32]2[C:44]([OH:46])=[O:45])[CH2:25][CH2:24][CH2:23]1
Reactant: Cc1nnc2ccc3c(cc(C(=O)OCc4cc(Cl)cc(CN5CCC5)c4)n3Cc3cc(Cl)cc(CN4CCC4)c3)n12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cc(Cl)cc(CN4CCC4)c3)n12
Reaction time: 1 h

Procedure:
3-(Azetidin-1-ylmethyl)-5-chlorobenzyl 6-[3-(azetidin-1-ylmethyl)-5-chlorobenzyl]-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylate trifluoroacetate salt (0.080 g, 0.085 mmol, from Step 8) in THF (2 mL) was treated with 1.0 M solution of NaOH in water (2 mL, 2 mmol). After 1 hour, MeCN and MeOH were added to make the reaction monophasic, and the product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (35 mg, 100%).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([Cl:13])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[OH:25]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=1[O:25][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:7][C:8]=1[Cl:13]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Cl)c(O)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2Cl)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 1 step (iii).
Reaction SMILES: C([O:4][CH:5]1[C:9](=[O:10])[C:8]([CH2:11][CH2:12][CH:13]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][CH2:6]1)(=O)C.CC(C)(O)[C:25]#[N:26].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:20]([O:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH:8]1[CH:7]([C:25]#[N:26])[CH2:6][CH:5]([OH:4])[C:9]1=[O:10])(=[O:22])[CH3:21]
Reactant: CC(C)(O)C#N
Reactant: CCCCCC(CCC1=CCC(OC(C)=O)C1=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(CCC1C(=O)C(O)CC1C#N)OC(C)=O
Yield: 96.9 %

Procedure:
5-Acetoxy-2-(3-acetoxyoctyl)cyclopent-2-enone (15.5 g.) [prepared as described in (h) above] acetone cyanohydrin (6.0 g.), aqueous sodium carbonate solution (10.0% w/v; 5 ml.) and methanol (75 ml.) were stirred together and heated at reflux for 4 hours. Methanol was removed in vacuo, water (50 ml.) was added and the mixture extracted with diethyl ether. The ethereal extract was washed with water, dried with magnesium sulphate and evaporated in vacuo to give 2-(3-acetoxyoctyl)-3-cyano-5-hydroxycyclopentanone (14.3 g.) which was used as starting material in the following preparation (k) of 3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentane carbonitrile without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CCO[Si](C)(C)C(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazole.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:32]([C:29]1[CH:28]=[N:27][C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:31][CH:30]=1)#[N:33]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: N#Cc1cnc(N)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ncc(C#N)cn1)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of phenyl 7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 3, 50 mg, 0.152 mmol) in THF (1.5 ml) was treated with 2-amino-5-cyanopyrimidine (45.7 mg, 0.381 mmol), cooled to 0° C. and treated with LHMDS (1M in THF, 0.305 ml, 0.305 mmol). The reaction mixture was stirred at 0° C. for 1 h, allowed to warm to room temperature and stirred for 45 min. More 2-amino-5-cyanopyrimidine (22.9 mg, 0.190 mmol) and LHMDS (1M in THF, 0.152 ml, 0.152 mmol) were added, the reaction mixture was stirred for 35 min, quenched by addition of sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100). The product containing fractions were concentrated and re-purified by reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 95:5 to 5:95). The product containing fractions were treated with sat. aq. NaHCO3, concentrated until the organic solvent had been removed and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a white solid. (UPLC-MS 1) tR 0.87 min; ESI-MS 355.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 2.0 g (6.51 mmol) of 3-[3-(imidazo-[1,2-a]pyridin-5-ylthio)propyl]thiazolidine-2,4-dione and 0.59 ml (6.51 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.65 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/1→1/4) to yield 1.57 g (66.7%, light orange oily substance) of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].O>CN(C)C=O>[CH3:24][N:25]([CH3:27])/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)/C=C/N(C)C)cc2)CC1
Temperature: 25 °C

Procedure:
The product from Example 26A (2.14 g, 7.42 mmol) and N,N-dimethylformamide dimethylacetal (1.42 g, 11.9 mmol) in N,N-dimethylformamide (20 mL) were heated at 100° C. for 16 h. The solution was cooled to room temperature, and water (20 mL) was added over a period of 10 min. The precipitate was collected by filtration, washed with water (3×20 mL), and dried in vacuo at 50° C. for 24 h to give crude product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.11-1.21 (m, 5H), 1.43-1.55 (m, 2H), 1.63-1.82 (m, 5H), 2.22 (d, J=6.76 Hz, 2H), 2.43-2.47 (m, 1H), 2.90 (s, 3H), 3.12 (s, 3H), 4.07 (q, J=7.06 Hz, 2H), 5.79 (d, J=12.27 Hz, 1H), 7.27 (d, J=8.59 Hz, 2H), 7.67 (d, J=12.27 Hz, 1H), 7.79 (d, J=8.59 Hz, 2H); MS (ESI) m/z 344.1.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:23][O:22][C:10]2=[CH:11][CH:12]=[C:13]3[C:17]([N:16]([CH2:18][CH:19](O)[CH3:20])[N:15]=[CH:14]3)=[C:9]2[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>C1COCC1.CS(C)=O>[N:40]([CH:19]([CH3:20])[CH2:18][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]3[O:22][CH2:23][CH:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[CH2:8][C:9]3=2)[CH:14]=[N:15]1)=[N+:41]=[N-:42]
Reactant: CCOC(C)OC1COc2ccc3cnn(CC(C)O)c3c2C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(C)OC1COc2ccc3cnn(CC(C)N=[N+]=[N-])c3c2C1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To solution of the product from Step G (0.52 g, 1.6 mmol) and triethylamine (1.12 mL, 8.1 mmol) in anhydrous THF (75 ml) at 0° C. was added methanesulfonic anhydride (0.71 g, 4.05 mmol). The mixture was stirred for 20 min and sodium azide (2.11 g, 32.4 mmol) was added along with DMSO (20 mL). The THF was removed (in vacuo) and the reaction mixture was heated at 90° C. for 3 h. The mixture was cooled, poured into a saturated solution of sodium bicarbonate (150 mL), and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), and evaporated to a residue that was purified by chromatography (silica, 10% EtOAc/hexane) to give an oil (0.40 g, 72%): LC/MS (+APCI) mz 346 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[C:7](=O)([O:10][CH:11]([CH3:13])[CH3:12])[O:8]C>CO>[C:7](=[O:8])([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[O:10][CH:11]([CH3:13])[CH3:12].[CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3]
Reactant: COC(=O)OC(C)C
Agent: CN(C)CCO
Solvent: CO
Product: CC(C)OC(=O)OCCN(C)C

Procedure:
In a preferred embodiment of the one-step process, bis[2-(N,N-dimethylamino)ethyl]carbonate is produced by the process comprising the step of reacting 2-(N,N-dimethylamino)ethanol with methyl isopropyl carbonate in the presence of a transesterification catalyst to form isopropyl 2-dimethylaminoethyl carbonate and methanol, wherein the 2-(N,N-dimethylamino)ethanol reacts with the isopropyl 2-dimethylaminoethyl carbonate to form bis[2-(N,N-dimethylamino)ethyl] carbonate and isopropanol, under conditions such that the methanol and isopropanol are removed continuously by distillation so that the reactions proceed toward formation of bis[2-(N,N-dimethylamino)ethyl] carbonate.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[CH:37]=[O:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([O:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=2[C:37]([OH:6])=[O:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C=O)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C(=O)O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of sodium chlorite (320 mg; 3.54 mmol; 5.5 eq.) and sodium dihydrogenphosphate (278 mg; 2.32 mmol; 3.6 eq.) in water (2 mL) was added dropwise to a mixture of 2-methyl-2-butene (0.64 mL) and (S)-3-(5-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (208 mg; 0.64 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 16 hours and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water and the pH made acidic with 0.1M HCl. The mixture was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (202 mg, 93%) as a white solid. HPLC (max plot) 94.3%; Rt 3.89 min. UPLC/MS: (MS−) 338.4 ([M−H]−).
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)[C@@H](O)C[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O.C=O.[CH:32]([O:34][CH:35]1[CH2:58][CH2:57][C@@:56]2([CH3:59])[CH:37]([CH2:38][CH:39]([O:64][CH:65]=[O:66])[C@@H:40]3[C@@H:55]2[CH2:54][CH:53]([O:60][CH:61]=[O:62])[C@@:52]2([CH3:63])[C@H:41]3[CH2:42][CH2:43][C@@H:44]2[C@H:45]([CH3:51])[CH2:46][CH2:47][C:48](O)=[O:49])[CH2:36]1)=[O:33].C(Cl)(=O)C([Cl:70])=O>>[CH:32]([O:34][CH:35]1[CH2:58][CH2:57][C@@:56]2([CH3:59])[CH:37]([CH2:38][CH:39]([O:64][CH:65]=[O:66])[C@@H:40]3[C@@H:55]2[CH2:54][CH:53]([O:60][CH:61]=[O:62])[C@@:52]2([CH3:63])[C@H:41]3[CH2:42][CH2:43][C@@H:44]2[C@H:45]([CH3:51])[CH2:46][CH2:47][C:48]([Cl:70])=[O:49])[CH2:36]1)=[O:33]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(OC=O)CC4CC(OC=O)CC[C@]4(C)[C@H]3CC(OC=O)[C@]12C
Agent: C=O
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Product: C[C@H](CCC(=O)Cl)[C@H]1CC[C@H]2[C@@H]3C(OC=O)CC4CC(OC=O)CC[C@]4(C)[C@H]3CC(OC=O)[C@]12C

Procedure:
By a standard technique using cholic acid and formalin, 3,7,12-triformyloxycholanoic acid was synthesized. It was then chlorinated using oxalyl chloride. The crude product thus obtained was used in the subsequent step of esterification without purification.