Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC)([O:17]C)[O:15]C>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([B:14]([OH:17])[OH:15])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 583.8 %

Procedure:
To a mixture of 5-bromo-2-fluoro-pyridine (1.71 g, 6.20 mmol) in dry ether (100 mL) was added n-BuLi (1.6 M in hexane, 41.4 mL, 0.0663 mol) at −78° C. After 30 minutes, trimethyl borate (8.2 mL, 0.0722 mol) was added to the above mixture and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with water and brine and acidified with 10% HCl until pH=8. The mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, concentrated to give 5.1 g (60%) of the desired product. The crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH:9]=[O:10].[NH4+].[Cl-]>C1COCC1>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[C:9](=[O:10])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1c(F)cccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(=O)c1c(F)cccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (18 mL of 2 M in Et2O, 35 mmol) is added to a solution of 2-bromo-6-fluoro-benzaldehyde (6.0 g, 30 mmol) in THF (40 mL) at −78° C. and the mixture is stirred for 1 hour at 0° C. The mixture is poured into saturated NH4Cl and extracted with EtOAc. The resulting crude alcohol is oxidized directly by Swem oxidation to yield 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one. 1H NMR (CDCl3) 7.38 (d, 1H), 7.22 (m, 1H), 7.03 (t, 1H), 3.10 (m, 1H), 1.11 (d, 6H).
Reaction SMILES: S(Cl)(Cl)=O.Cl[C:6]1[C:11]([C:12](O)=O)=[CH:10][N:9]=[CH:8][CH:7]=1.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[H-].[Na+].[CH3:24]N(C)C=O>O>[CH3:24][C:12]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[S:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=C(O)c1cnccc1Cl
Reactant: CN(C)C=O
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc2ccncc2c1C
Reaction time: 18 h
Yield: 17 %

Procedure:
Thionyl chloride (100 mL) was added to 4-chloronicotinic acid (22.4 g), and the mixture was stirred with heating under reflux for 4 hr, and concentrated under reduced pressure. To a solution (300 mL) of the residue in methylene chloride were added N,O-dimethylhydroxylamine hydrochloride (13.8 g) and triethylamine (60 mL), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the reaction mixture was extracted with methylene chloride. The extract was dried over sodium sulfate, and concentrated under reduced pressure. To a solution (300 mL) of the residue in tetrahydrofuran was added a 3.0 M solution (54 mL) of methylmagnesium chloride in ether at −78° C. and the mixture was stirred under nitrogen atmosphere at room temperature for 10 hr. The reaction mixture was acidified with aqueous sodium carbonate solution to pH=9, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure to give a colorless oil. To a mixture of the obtained oil, ethyl mercaptoacetate (21 mL) and anhydrous N,N-dimethylformamide (200 mL) was added sodium hydride (60%, oily, 7.34 g) at 5° C. over 30 min, and the mixture was stirred at 5° C. for 20 min then at room temperature for 18 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from petroleum ether/ethyl acetate to give the title object compound (5.45 g, 17%) as a white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]12[CH2:15][CH2:14][C:11]([C:16]3[NH:17][C:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=4)=[C:19]([C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[N:20]=3)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)=[O:7]>C1COCC1.CO.O>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([C:19]3[N:20]=[C:16]([C:11]45[CH2:14][CH2:15][C:8]([C:6]([OH:7])=[O:5])([CH2:9][CH2:10]4)[CH2:13][CH2:12]5)[NH:17][C:18]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: COC(=O)C12CCC(c3nc(-c4ccc5c(c4)OCO5)c(-c4cccc(C)n4)[nH]3)(CC1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2-c2ccc3c(c2)OCO3)n1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Lithium hydroxide monohydrate (0.020 g, 0.487 mmol) was added to a solution of 4-[4-benzo[1,3]dioxol-5-yl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-2-yl]-bicyclo[2.2.2]octane-1-carboxylic acid methyl ester (see Example 21; 0.150 g, 0.325 mmol) in a mixture of THF/MeOH/H2O (2/1/1, 4 mL). The mixture was stirred for 3 hours. Solvent was removed. Residue was diluted with water (30 mL). Citric acid was added to the solution to make the pH lower than 7. The aqueous solution was extracted with ethyl acetate. Ethyl acetate extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.140 g (99%) of the title compound as a yellow solid. MS (ESP+) m/z 432.2 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.72 (m, 1H), 7.33 (d, 1H, J=7.7 Hz), 7.22 (d, 1H, J=7.7 Hz), 6.98 (m, 3H), 6.05 (s, 2H), 2.64 (s, 3H), 2.11 (m, 6H), 1.99 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=1
Reactant: CC(C)(C)COc1ccc(CBr)cc1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)(C)COc1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1
Product: Cl

Procedure:
Use a method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 1-bromomethyl-4-(2,2-dimethylpropoxy)-benzene. Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 390 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[CH3:19][O:20][C:21]1[N:28]=[CH:27][CH:26]=[C:25]([O:29][CH:30]([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:22]=1[CH:23]=O>CO.C(O)(=O)C>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][N:6]1[C:5](=[O:18])[C:4]2[CH:3]=[C:2]3[NH:1][C:23]([C:22]4[C:21]([O:20][CH3:19])=[N:28][CH:27]=[CH:26][C:25]=4[O:29][CH:30]([CH3:38])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:11][C:10]3=[CH:9][C:8]=2[C:7]1=[O:12]
Reactant: COc1nccc(OC(C)Cc2ccccc2)c1C=O
Reactant: CN(C)CCN1C(=O)c2cc(N)c(N)cc2C1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(OC(C)Cc2ccccc2)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
5,6-Diamino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione (0.47 g, 1.88 mmol) was dissolved in MeOH (30 mL) and acetic acid (10 mL). 2-Methoxy-4-((1-phenylpropan-2-yl)oxy)nicotinaldehyde (0.51 g, 1.88 mmol) was added under air at rt. The reaction mixture was stirred at rt under air overnight. The volatile was removed. The residue was subjected to column chromatography (silica-gel, CH2Cl2/MeOH=17/3 v/v) to give a white solid product, 0.65 g, 69.2% yield. MS: 500.3 [M+H]+. 1H-NMR (DMSO-d6, 500 MHz): δ 13.23 (s, 1H), 8.20 (d, 1H, J=6.0 Hz), 8.12 (s, 1H), 7.95 (s, 1H), 7.09-7.07 (m, 1H), 7.11-7.95 (m, 5H), 4.84-4.81 (m, 1H), 3.82 (s, 3H), 3.72 (t, 2H, J=6.5 Hz), 2.78 (d, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.5 Hz), 2.19 (s, 6H), 1.17 (d, 3H, J=6.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].N1C=CC=CC=1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:23])(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
188 mg (0.40 mmol) of (−)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-1a-1)) was dissolved in 8 ml of methylene chloride, followed by the addition of 39 μl (0.48 mmol) of pyridine and 51 μl (0.44 mmol) of benzoyl chloride under 0° C. The reaction mixture was stirred at room temperature for 1.5 hours. To the reaction solution, 10 ml of saturated aqueous solution of ammonium chloride was added and extracted with 50 ml of methylene chloride. The extract was washed with 20 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:1 mixture of ethyl acetate and hexane) to obtain 228 mg of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:21])=[C:16]([Cl:22])[CH:15]=2)[C:6](O)=[O:7].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[NH2:44][CH:45]1[CH2:50][C:49]([CH3:52])([CH3:51])[N:48]([CH3:53])[C:47]([CH3:55])([CH3:54])[CH2:46]1>CN(C=O)C.O>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[Cl:22])[NH:13][C:12]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][CH:45]3[CH2:46][C:47]([CH3:54])([CH3:55])[N:48]([CH3:53])[C:49]([CH3:52])([CH3:51])[CH2:50]3)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])=[CH:20]2
Reactant: COc1cc(C(=O)O)ccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A mixture of 3-methoxy-4-(5,6-dichloro-1H-indol-2-yl)-benzoic acid (0.15 g, 0.45 mmol), WSC (0.094 g, 0.5 mmol), HOAT (0.067 g, 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (0.15 g, 0.9 mmol) in DMF (2 ml) was stirred at 50° C. for 18 h. The mixture was then poured in a large volume of water and extracted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; CH2Cl2—MeOH—NH4OH: 91.5-7.5-1) then crystallised in di-isopropyl ether to afford 0.13 g (0.26 mmol. yield 59%) of the title compound, mp=260° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].O1CCC(=O)CC1.C1(=O)CCCCC1.Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(NC(=O)OC(C)(C)C)CCOCC1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: CCO
Solvent: O=C1CCCCC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCOCC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a mixture of tert-Butyl {4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-yl}carbamate (3.0 g, prepared according to the general methods of Parts A through F of Example 54 using tetrahydro-4H-pyran-4-one in lieu of cyclohexanone in Part A), hydrochloric acid (12.2 mL of 2.8 M in ethanol), and ethanol (18 mL) was heated at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and was then concentrated under reduced pressure. The residue was combined with isopropanol (100 mL). A solid was isolated by filtration to provide 2.56 g of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]tetrahydropyran-4-amine as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[Cl:12].Cl[CH2:14][C:15]([CH2:17]Cl)=O.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH2:35][CH2:36][OH:37])=[CH:32][CH:33]=2)[C:23]([C:38]#[N:39])=[C:22]([SH:40])[N:21]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH2:35][CH2:36][OH:37])=[CH:32][CH:33]=2)[C:23]([C:38]#[N:39])=[C:22]([S:40][CH2:17][C:15]2[N:11]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([Cl:12])[CH:4]=3)[S:10][CH:14]=2)[N:21]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(Nc3ccc(F)c(Cl)c3)n2)c(C#N)c1-c1ccc(OCCO)nc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
209 mg (0.67 mmol) of 4-fluoro-3-chlorophenylthiourea and 89 mg (0.70 mmol) of 1,3-dichloroacetone are dissolved in 5 ml of DMF, and the reaction solution is stirred at 80° C. for 3 h. After cooling, 209 mg (0.67 mmol) of the compound from example 2A and 224 mg (2.67 mmol) of sodium bicarbonate are added, and the mixture is stirred at RT for a further 20 h. The mixture is then filtered through a paper filter, and sat. sodium bicarbonate solution (5 ml) is added to the filtrate. The aqueous phase is extracted with ethyl acetate (three times, 5 ml each). The combined organic phases are dried over sodium sulphate, and the solvent is removed on a rotary evaporator.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:17][CH3:18])[CH:12]=3)[O:7][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[NH:22]([CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[NH2:23]>C1COCC1>[ClH:1].[CH3:18][O:17][C:11]1[CH:10]=[CH:9][C:8]2[O:7][C:6]3[C:15]4[C:14](=[N:23][N:22]([CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)[C:2]=4[CH:3]=[CH:4][C:5]=3[N+:19]([O-:21])=[O:20])[C:13]=2[CH:12]=1
Reactant: COc1ccc2oc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Reactant: NNCCN1CCCC1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)-c1nn(CCN3CCCC3)c3ccc([N+](=O)[O-])c(c13)O2
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 12.2 g of 1-chloro-7-methoxy-4-nitro-9H-xanthen-9-one and 11.0 g of 1-(2-hydrazinoethyl)pyrrolidine in 200 ml of THF was stirred 20 hours at room temperature. The orange liquor was decanted, freed of solvent under reduced pressure, and the residue, in chloroform, was chromatographed over silica gel, eluting with chloroform-methanol (25:1 by volume). The desired fractions yielded the free base of the title compound, mp 140°-142° C.
Reaction SMILES: [CH:1]([O-:3])=[O:2].[NH4+].[N:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C@H:9]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N+]=[N-]>C(O)C.[Pd]>[C:14]([OH:16])(=[O:15])[C:1]([OH:3])=[O:2].[NH2:5][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][C@H:9]1[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: O=C[O-]
Reactant: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H](N)[C@H](NC(=O)OC(C)(C)C)C1
Product: O=C(O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7.5% Pd—C (100 mg) and ammonium formate (444.1 mg) were added at room temperature to a solution (10 mL) of ethyl (1S,3R,4S)-4-azido-3-[(t-butoxycarbonyl)amino]cyclohexanecarboxylate (1.0 g) in ethanol, followed by stirring at 50° C. for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated, to thereby yield 911.0 mg of crude ethyl (1S,3R,4S)-4-amino-3-t-butoxycarbonylaminocyclohexanecarboxylate. The crude product was dissolved in ethyl acetate (20 mL), and anhydrous oxalic acid (286.4 mg) was added to the solution, followed by stirring at room temperature for 16 hours. The formed crystals were recovered by filtration and dried, to thereby yield 1.16 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:23])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)cc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)acrylic acid (936 mg, crude) in DMF (10 mL) was added was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (442 mg), HOBt (588 mg), and EDCI (676 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1) to give (2E)-3-(4-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (945 mg) as pale yellow form.
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([Sn:15](N=C=S)([N:20]=[C:21]=[S:22])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].C([OH:28])C>>[OH:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:28][Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:11][CH2:12][CH2:13][CH3:14])[N:20]=[C:21]=[S:22]
Reactant: CCCC[Sn](CCCC)(N=C=S)N=C=S
Reactant: CCO
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn](O)(CCCC)O[Sn](CCCC)(CCCC)N=C=S
Reaction time: 18 h
Yield: 86 %

Procedure:
A mixture of di-n-butyltin oxide (2.14 g, 8.6 mmol) and di-n-butyltin diisothiocyanate (1.0 g, 2.8 mmol) in ethanol (30 mL) was heated to reflux for 6 hours during which time the white slurry became a clear solution. The reaction mixture was concentrated via rotary evaporator to a solid which was pulverized and left exposed at ambient temperature for 18 hours. The powder was recrystallized from hexanes at 0° C. to give the title compound as a white solid (2.74 g, 86%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[C:29]([O:33][C:34]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:41][CH:42]=1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-tert.butyloxycarbonyl-aniline Rf value: 0.4 (aluminium oxide, methylene chloride/ethanol=40:1) C29H28N2O5
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:27]=[O:28])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([O:8][C@H:9]([C@@H:26]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:27]([OH:28])[CH3:37])[CH2:10][O:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](C)O)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of (S)-methyl 3-((2S,3R)-2,3-bis(benzyloxy)-4-oxobutoxy)-2-((tert-butoxycarbonyl)amino)propanoate (0.980 g, 1.95 mmol) in DCM (18.61 ml) at −78° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (Et2O) (1.30 ml, 3.91 mmol) and the reaction was stirred at −70° C. for 1 h, warmed slowly to −20° C. over 2 h, and then quenched at −20° C. with H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (0.475 g, 47%): 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 10H), 5.43 (d, J=8.6 Hz, 1H), 4.71 (d, J=14.0 Hz, 1H), 4.69 (d, J=14.4 Hz, 1H), 4.55 (dd, J=11.5, 2.6 Hz, 2H), 4.49-4.41 (m, 1H), 3.96-3.84 (m, 2H), 3.75 (dd, J=10.1, 5.0 Hz, 1H), 3.72 (s, 3H), 3.71-3.63 (m, 3H), 3.32-3.29 (m, 1H), 2.26 (d, J=6.3 Hz, 1H), 1.45 (s, 9H), 1.14 (d, J=6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.20, 155.58, 138.36, 138.21, 128.59, 128.53, 128.21, 128.07, 128.05, 127.89, 82.88, 80.16, 78.55, 74.94, 73.18, 71.71, 71.34, 67.04, 54.16, 52.58, 28.46, 20.30; ESIMS m/z 516.3 ([M−H]−).
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:17])=O.Cl.S(=O)=O>>[C:1]([Cl:17])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Product: CCCCCCCCCCCC(=O)Cl
Reaction time: 4 h
Yield: 98 %

Procedure:
To a stirred mass of lauric acid (200 g, 0.999 gmol) and N-lauroyl glycenic lauric anhydride (Formula IV, RCO=lauroyl, R═C11) from step I (0.6 g, 0.0013 gmol) at 25° C. under nitrogen blanket, thionyl chloride (123 g, 1.03 gmol) was added slowly at 25° C. and atmospheric pressure over a period of 2 hours maintaining temperature below 25° C. The hydrochloric acid and sulfur dioxide generated during the process was intermittently scrubbed in a gas scrubber containing caustic lye. The reaction mixture was stirred for additional 4 hours at the reaction temperature. The progress of reaction was monitored by measuring alkanoyl chloride formation and residual free fatty acid (Sidney Siggia and J. Gordon Hanna, “Quantitative Organic Analysis Via Functional Groups”, 4th Edition (Pg. 223-230), John Wiley & Sons (1979)). Nitrogen gas was purged through the reaction mass for 3 hours to remove the residual traces of sulfur dioxide, hydrogen chloride gas and unreacted thionyl chloride. At the end of this procedure lauroyl chloride (214 g, 98.0%) was obtained as practically colorless product. The detailed analysis is given in the Table 1.