Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:17][CH:18]=O)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(C)C>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH:15]([NH:17][CH3:18])[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Solvent: CSC
Solvent: C1CCOC1
Product: CNC(C)C1(c2ccc(Cl)c(Cl)c2)CCCCC1
Product: Cl
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To the refluxing solution of N-{1-[1-(3,4-dichloro-phenyl)-cyclohexyl]-ethyl}-formamide (5.2 g, 17.32 mmol) in anhydrous THF (75 mL) was added slowly BH3.SMe2 (2N solution in THF, 26 mL, 51.96 mmol). The solution was stirred at 70° C. for 20 mins then a distillation head was installed. The solution was refluxed for 2 h, during which SMe2 was distilled, and the solution was cooled to R.T. and concentrated using a rotary evaporator. The pale yellow residue was cooled to 0° C. and added slowly to methanol (20 mL) to destroy the excess borane. The resulting clear solution was added to 6N aqueous HCl (50 mL) and heated to reflux for 40 minutes, then cooled to room temperature. The solid that formed was filtered and washed with water (2×50 mL), followed by slurrying in ethyl ether (200 mL) and filtration to give 48 E1 as a white solid. (4.04g, 72.5%). Note: Same reaction was run on a 50 g scale with 70% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: Nc1ccccn1
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)Nc2ccccn2)cc1[N+](=O)[O-]

Procedure:
4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol), 2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) were allowed to stir in DCM (10 mL) for 48 h to form 4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purified via silica column chromatography using 0 to 100% EtOAc in hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:30])=[C:14]([NH:19][C:20](=O)[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:31])=[CH:4][CH:3]=1>C(O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]3[O:10][C:9]([CH3:31])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:12]=3[C:13]=2[CH3:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Solvent: CCO
Product: COc1ccc(CNc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Yield: 75 %

Procedure:
By using N-[3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]-4-methoxybenzamide, the title compound was synthesized according to Example 2b. Yield: 75%. Melting point: 100-102° C. (Ethanol).
Reaction SMILES: [CH3:1][O:2]/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].[Br:16]N1C(=O)CCC1=O>CO>[CH3:1][O:2]/[C:3](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][Br:16])=[CH:4]/[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)/C=C(/OC)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COC(=O)/C=C(/OC)c1ccccc1CBr

Procedure:
200 g (0.97 mol) of methyl (E)-β-methoxy-2-methylcinnamate and 190 g (1.07 mol) of N-bromosuccinimide which has been washed with methanol and dried, in 2 l of dry tetrachloromethane, are irradiated with a 300 watt UV lamp for 75 min, during which the solution begins to reflux.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][N:35]=1)[C:31]#[N:32].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:31]([C:30]1[CH:33]=[CH:34][N:35]=[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)[CH:29]=1)#[N:32]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1cc(C#N)ccn1

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloroisonicotinonitrile as starting materials and by operations similar to those of Example 303-3 and Example 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([C:10]2[CH:15]=[C:14]([C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=2[OH:27])([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[Cl-:30].Cl[C:32]1[CH:37]=[CH:36][C:35]([N+:38]#[N:39])=[C:34]([N+:40]([O-:42])=[O:41])[CH:33]=1>>[Cl:30][C:37]1[CH:32]=[CH:33][C:34]([N+:40]([O-:42])=[O:41])=[C:35]([N:38]=[N:39][C:12]2[CH:13]=[C:14]([C:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)([CH3:18])[CH3:17])[CH:15]=[C:10]([C:7]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)([CH3:8])[CH3:9])[C:11]=2[OH:27])[CH:36]=1
Reactant: [Cl-]
Reactant: COc1ccc(C(C)(C)c2ccc(O)c(C(C)(C)c3ccc(OC)cc3)c2)cc1
Reactant: N#[N+]c1ccc(Cl)cc1[N+](=O)[O-]
Product: COc1ccc(C(C)(C)c2cc(N=Nc3cc(Cl)ccc3[N+](=O)[O-])c(O)c(C(C)(C)c3ccc(OC)cc3)c2)cc1

Procedure:
The title compound is prepared according to the procedure of Example 23 using 45 g of 2,4-di-(4-methoxy-α-cumyl)phenol prepared in Example 7 and 131 g of the diazonium salt solution of Example 11. The desired product is obtained in a yield of 49.1 g as a crimson red solid melting at 150-152° C. The structure is confirmed by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.17 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6]C)=[O:5].[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].Cl>[OH-].[Na+]>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:13]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)NCCC(=O)O
Reaction time: 4 h

Procedure:
558 mg (4.03 mmol) of methyl 3-aminopropionate was dissolved in 20 ml of 1 N aqueous sodium hydroxide solution. 362 mg (3.00 mmol) of pivaloyl chloride was immediately added to the obtained solution, and they were stirred for 4 hours. 15 ml of 2 N aqueous hydrochloric acid was added to the reaction mixture. After extracting with ethyl acetate 3 times followed by drying under anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C(O)(=O)C.C(OCC)C.[Pt]=O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: Clc1cccc2ncccc12
Agent: O=[Pt]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Clc1cccc2c1CCCN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of 5-chloroquinoline (10.0 g) and platinum oxide (50 mg) in acetic acid was shaken under a hydrogen atmosphere at room temperature for 4 hours. The mixture was diluted with diethyl ether and filtered through Celite. The volatiles were removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (3×300 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica gel and the fractions containing product were combined and concentrated under reduced pressure to provide 7.0 g (69%) of the desired compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1)=O.[N:16]1([CH2:22][CH2:23][CH2:24][NH:25][C:26]([NH2:28])=[S:27])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>O1CCOCC1>[O:19]1[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][N:25]([C:26]2[S:27][CH:2]=[C:3]([C:5]3[O:9][N:8]=[C:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:6]=3)[N:28]=2)[C:43]([C:39]2[S:38][CH:42]=[CH:41][CH:40]=2)=[O:44])[CH2:21][CH2:20]1
Reactant: O=C(CBr)c1cc(-c2ccccc2)no1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(c1cccs1)N(CCCN1CCOCC1)c1nc(-c2cc(-c3ccccc3)no2)cs1
Temperature: 80 °C
Yield: 53.8 %

Procedure:
A mixture of 2-bromo-1-(3-phenylisoxazol-5-yl)ethan-1-one (160 mg, 0.6 mmol) and (3-morpholin-4-yl-propyl)-thiourea (122 mg, 0.6 mmol) in dry dioxane (5 ml) was heated at 80° C. for 2 h, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5 mL) followed by the addition of N,N-diisopropylethylamine (209 μL, 1.2 mmol) and thiophene-2-carbonyl chloride (96 μL, 0.9 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (155 mg) as an off-white solid as the hydrochloride salt. LC/MS (ESI) m/z 481.1 [M+H]. HPLC retention time (Method B)=2.94 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[CH2:11][CH2:12][NH2:13].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:11][CH2:12][NH2:13]
Reactant: Cc1c(CCN)[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1c2ccccc2NC1CCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of 2-(3-methylindol-2-yl)ethylamine (2.5 g) in acetic acid [25 ml) at 15° C. was added sodium cyanoborohydride (1.62 g) in one portion. The solution was stirred at room temperature. After 3 hours, sodium cyanoborohydride (1.0 g) was added and the mixture was stirred at room temperature for 12 hours. After dilution with ice-water, the reaction mixture was made basic with sodium hydroxide pellets and extracted three times with ether. The ether layer was washed with water and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 2-(2,3-dihydro-3-methylindol-2-yl)ethylamine (1.80 g) as an oil. The oil was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:15](COCC[Si](C)(C)C)[C:14]([O:24][C@H:25]3[C@H:29]4[O:30][CH2:31][C@@H:32]([OH:33])[C@H:28]4[O:27][CH2:26]3)=[N:13][C:5]2=[N:6][C:7]=1[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:15][C:14]([O:24][C@H:25]3[C@H:29]4[O:30][CH2:31][C@@H:32]([OH:33])[C@H:28]4[O:27][CH2:26]3)=[N:13][C:5]2=[N:6][C:7]=1[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCCC3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(C3=CCCC3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 54 h

Procedure:
To (3R,3aR,6R,6aR)-6-((6-chloro-5-(cyclopent-1-en-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (15 mg, 0.030 mmol) in anhydrous DCM (0.55 mL) was added TFA (0.55 mL, 7.13 mmol). The solution stirred at RT for 54 h. The reaction solution was evaporated under reduced pressure. Flash chromatography utilizing a 4 g silica RediSep Rf® Gold column and employing a 0-20% (1% NH4OH in MeOH)/DCM gradient afforded the title compound. LC-MS: calculated for C17H18ClN3O4 363.10 observed m/e: 364.11 (M+H)+ (Rt 1.20/2.0 min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28](O)(=O)C.IC(C)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:28])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CC(C)I
Solvent: CCO
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a mixture of 5-((S)-1-benzyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (18.0 g, 1.0 eq.) and acetic acid (28 mL, 10 eq.) in ethanol (500 mL) was added palladium on activated charcoal (10% in mass, 2.0 g, 0.04 eq.) and the reaction vessel was flushed with hydrogen (1 Atm). The reaction mixture was stirred 18 h at room temperature and then filtered off and concentrated in vacuo. The residue (28.4 g) was dissolved in dimethylformamide (500 mL) and potassium carbonate was added. The mixture was stirred 15 min at room temperature. Then 2-iodopropane (42 g, 5.0 eq.) was added and the mixture was stirred 4 h at 50° C. The reaction mixture was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in acetone, filtered and the filtrate was evaporated in vacuo then purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 9.3 g (59%) of the desired product as light brown solid. MS (m/e): 317.4 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]=O.Cl.[CH3:39][NH:40][CH3:41]>C(O)C>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[C:29]=3[CH2:39][N:40]([CH3:36])[CH3:41])[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: CNC
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: C[C@@H](O[C@H]1CN(C2=C(CN(C)C)C(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
In a pressure tube, 50 mg (0.0997 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F), 10.5 mg (0.3489 mmol) paraformaldehyde, and 20.3 mg (0.2493 mmol) dimethylamine hydrochloride was dissolved in ethanol (4 mL). The tube was sealed and heated in an oil bath for 3 hr at 90° C. The reaction mixture was cooled to RT, the tube was opened and the solvent removed under vacuum. The residue was partitioned between of 5 mL 1N aq. NaOH and EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to provide a yellow oil. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The more polar UV active band was isolated to afford the title compound as a glassy yellow solid. 1H-NMR (CD3OD) rotamers: δ: 1.44 (d, 3H, 6.5 Hz), 2.4-2.90 (m, 10H), 3.4-4.6 (m, 8H), 4.82 (br. s, 1H), 6.97 (t, 2H, 8.5 Hz), 7.23 (br. s, 2H), 7.69 (s, 2H), 7.80 (s, 1H)ppm. MS: 559.1 (MH+) observed.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:25][C:26]([O:28][C:29](C)(C)C)=[O:27]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:3]2[C:2]([Cl:1])=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[CH:9]3)=[N:4]2)=[CH:16][CH:15]=1
Reactant: Clc1c2ccccc2nn1-c1ccc(OC[C@@H]2CCCN2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: COC(=O)CN1CCC[C@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 68.6 %

Procedure:
The title compound was prepared from product from 3-chloro-2-[4-((S)-1-pyrrolidin-2-ylmethoxy)-phenyl]-2H-indazole (0.33 g, 0.94 mmol) and t-butyl bromoacetate (0.22 g, 1.1 mmol) using the procedure of step 1 of the Example 15 to provide the title compound (0.258 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1COCC1.[F:53][C:54]1[CH:61]=[CH:60][C:57]([CH2:58][NH2:59])=[CH:56][CH:55]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22]([NH:59][CH2:58][C:57]3[CH:60]=[CH:61][C:54]([F:53])=[CH:55][CH:56]=3)=[O:23])=[CH:14][C:12]=2[N:13]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(o1)c(C(=O)NCc1ccc(F)cc1)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 19.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.060 g, 0.159 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.102 g, 0.318 mmol), TEA (0.032 g, 0.318 mmol), THF (5.0 mL), DMF (1.0 mL), 4-fluoro benzyl amine (0.035 g, 0.318 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 2.49 (s, 3H), 4.55 (d, J=5.4 Hz, 2H), 6.22 (s, 1H), 7.13-7.16 (m, 2H), 7.41 (m, 3H), 8.44 (s, 2H), 8.61 (s, 1H), 11.22 (s, 1H), 11.76 (s, 1H); MS [M+H]+: 484.24.
Reaction SMILES: [CH3:1][C:2](/[CH:7]=[CH:8]\[CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH3:18][CH2:19]OCC.C([Li])C.[Cl-].[NH4+]>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4](=[O:6])[CH2:18][CH3:19]
Reactant: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]CC
Agent: [NH4+]
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 3.00 g. of trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid in 50 ml. ether at 0° under nitrogen is added 28.00 ml. of 0.9 M solution of ethyllithium in benzene. The solution is stirred for 1/2 hour at 0° and then overnight at room temperature. To the reaction mixture is added 50 ml. of ether and the resultant solution is added dropwise with stirring to 300 ml. saturated aqueous ammonium chloride. The organic layer is separated and is washed in turn with 50 ml. saturated aqueous ammonium chloride, 35 ml. water, and 35 ml. saturated aqueous sodium chloride. The solution is dried over calcium sulfate, is concentrated and is then purified by preparative thin layer chromatography (1:3 ether/hexane) and short path distillation (boiling point 100° at .18 mm.) to give 5,9,13-trimethyltetradeca-4,6-dien-3-one (85.4% trans-4, trans-6; 14.6% cis-4, trans-6.).
Reaction SMILES: [Na].[I-].[C:3]([CH2:5][CH2:6][P+:7](CCC#N)([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:9][O:10][CH3:11])#[N:4].O.C(Cl)(Cl)Cl>CO>[C:3]([CH2:5][CH2:6][P:7]([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:9][O:10][CH3:11])#[N:4]
Reactant: COCC[P+](CCC#N)(CCC#N)CCC#N
Agent: [I-]
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCCP(CCC#N)CCC#N

Procedure:
1.55 g of sodium are dissolved in 100 ml of absolute methanol under an atmosphere of argon and then 26 g (0.0685 mole) of tris-(β-cyanoethyl)-2-methoxyethyl-phosphonium iodide are added to this solution. The solution is refluxed for 4 hours. After the mixture has been poured into water, extraction is performed with three 40 ml portions of chloroform. The chloroform solution is dried over magnesium sulphate, the solvent is evaporated and the oily residue distilled in a high vacuum.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].[Cl:10][C:11]1[N:16]=[C:15]([C:17]([NH2:19])=[O:18])[CH:14]=[C:13](Cl)[N:12]=1.CCN(C(C)C)C(C)C>C(#N)C>[C:17]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([NH:2][CH2:3][C@H:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=1)(=[O:18])[NH2:19]
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Reactant: COC(=O)[C@@H](O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 76.1 %

Procedure:
To a mixture of the (S)-methyl 3-amino-2-hydroxypropanoate hydrochloride (0.333 g, 2.14 mmol) in acetonitrile (10 mL) was added 2,6-dichloropyrimidine-4-carboxamide (0.385 g, 2.01 mmol) and iPr2NEt (0.77 mL, 4.4 mmol). The mixture was heated at 50° C. overnight then cooled. The precipitated solid was filtered off, rinsed once with 2 mL acetonitrile, and air-dried to give (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate as a pale peach-colored powder (0.421 g, 1.53 mmol, 76% yield). LC/MS: m/z=275.1 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH:4]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=O.[CH3:20][CH:21]([CH2:44][CH2:45][CH2:46][CH3:47])[C:22]([C:24]1C=CC=CC=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:23]>O1CCCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:4]1[CH:3]([CH:1]=[CH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH2:44][CH2:45][CH2:46][CH3:47])[CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2
Reactant: O=CC1CCC2(OCCO2)C1CCCCCCCO
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)C(C)CCCC
Solvent: C1CCOC1
Product: CCCCC(C)C(=O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Yield: 101.8 %

Procedure:
A mixture of 7-formyl-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (3.88 g.) and 2-methylhexanoyl-methylenetriphenylphosphorane (6.0 g.) in dry tetrahydrofuran (30 ml.) was heated to reflux under nitrogen for 18 hours. The solvent was removed in vacuo and the residue triturated with petroleum ether (b.p. 60°-80° C.), allowed to stand at 0° C., filtered to remove triphenylphosphine oxide and the filtrate evaporated to give 6-(7-hydroxyheptyl)-7-(4-methyl-3-oxooct-1-enyl)-1,4-dioxaspiro[4,4]nonane (5.56 g), νmax 1620 cm-1, 1660 cm-1.