Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.CON(C)[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:5][C:4]([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])([CH3:8])[C:6]#[C:7][C:19]([C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: CON(C)C(=O)c1ccncc1
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a pre-cooled −78° C. stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy)silane (5.0 g, 0.03 mol) in dry THF (150 mL), n-BuLi (23.82 mL, 0.03 mol, 1.6 M in hexane) was added dropwise over a period of 10 minutes under an inert atmosphere. The reactions was stirred for 30 minutes at −78° C. and then a solution of N-methoxy-N-methylisonicotinamide (6.34 g, 0.03 mol) in dry THF (30 mL) was added to the reaction mixture and stirring was continued for an additional 40 min at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and finally concentrated in vacuo to obtain a residue. The residue was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (2.2 g, 27%) as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][C:16]([C:18]1[C:19]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:17])[O:5][C@H:6]([CH3:10])[C:7](O)=[O:8].O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:44]=3)=CC=2OC1>>[C:7]([C@H:6]([O:5][C:4]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16](=[O:17])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)=[C:2]([F:1])[CH:3]=1)[CH3:10])(=[O:8])[NH2:44]
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2cccc(C#N)c2)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.17) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[3-fluoro-4-({[2-(3-cyano-phenoxy)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])[CH3:28].C(N(CC)CC)C>ClCCl>[CH2:27]([O:29][C:30]([CH2:31][CH2:32][NH:33][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)=[O:34])[CH3:28]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1ccccc1-c1nc2nc(NCCC(=O)OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.0 g), β-alanine ethyl ester hydrochloride (1.10 g) and triethylamine (0.73 g) in dichloromethane (20 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) then water (10 ml), and the extracts back washed with dichloromethane (10 ml). The combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol:water to yield the title compound, 0.83 g, m.p. 142-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:11][C@@H:12]2[C@:21]3([CH3:22])[C@H:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][CH2:20]3)[CH2:15][CH2:14][C@@:13]2([CH3:26])O)[CH:6]=[C:7]([CH3:9])[CH:8]=1.Cl[Sn](Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]2[C:4]=1[C@@:13]1([CH3:26])[C@H:12]([CH2:11][S:10]2)[C@:21]2([CH3:22])[C@H:16]([C:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]1
Reactant: COc1cc(C)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(C)cc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Temperature: 0 °C
Yield: 55 %

Procedure:
To a solution of (1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)-sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13) (5.70 g, 15.1 mmol) in CH2Cl2 (300 mL) was added dropwise SnCl4 (1 M in CH2Cl2, 60 mL, 60 mmol) at −78° C. over 20 min. After complete addition, the reaction mixture was allowed to warm to 0° C. for 1 h. Water (50 mL) was added at 0° C. The organic layer was separated, dried (Na2SO4), and concentrated. Trituration with EtOAc (60 mL) gave (1R,10R,11S,16S)-3-methoxy-1,5,11,15,15-pentamethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 14) (1.44 g, batch 1) as a white solid. The filtrate was recrystallized to afford an additional batch (1.56 g, total yield 55%) as white crystals. 1H NMR (CDCl3): δ 6.52 (d, 1H), 6.38 (d, 1H), 3.78 (s, 3H), 3.30 (m, 1H), 2.84 (m, 1H), 2.76 (m, 1H), 2.20 (s, 3H), 1.84-1.40 (m, 8H), 1.38 (s, 3H), 1.34-1.00 (m, 3H), 0.95 (s, 3H), 0.86 (s, 3H), 0.86 (s, 3H). MS m/z 359 (C23H34OS+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=1[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[C:36](=[O:42])[CH:35]=[CH:34]2.C(OC(=O)C)C.[ClH:49]>C(OCC)(=O)C.CN(C=O)C>[ClH:49].[ClH:49].[CH3:41][N:37]1[C:38]2[C:33](=[CH:32][C:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:11]([CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[CH3:7])[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:40][CH:39]=2)[CH:34]=[CH:35][C:36]1=[O:42]
Reactant: Cn1c(=O)ccc2cc(OCCCCCBr)ccc21
Reactant: Cc1ccccc1CNCCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1CN(CCCCCOc1ccc2c(ccc(=O)n2C)c1)CCc1cccnc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Potassium carbonate(360 mg) and (2-methylbenzyl)-(2-pyridin-3-ylethyl)amine(591 mg) were added to a DMF solution (6.5 ml) of 6-(5-bromopentyloxy)-1-methyl-1H-quinolin-2-one(650 mg). The mixture was stirred at 60° C. for 8 hours. Ice water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and then saturated saline, dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate: methanol: aqueous ammonia=70:20:10:1). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution(1.0 ml) was added to an ethyl acetate solution(20 ml) of the residue, which was stirred at room temperature. The liquid was condensed to dryness under reduced pressure to give the title compound(270 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][N:22]1[CH2:21][CH2:20][N:16]2[C:17]3[CH:18]=[CH:19][C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:14]=[C:15]2[C:23]1=[O:24]
Reactant: OCCCBr
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCCO)C2=O)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-bromo-1-propanol, to give the desired product as a white solid (66%).
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([N+:28]([O-])=O)[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6].[H][H]>[Ni].C1COCC1>[C:5]([N:8]1[C:12]2=[CH:13][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:15][N:11]2[C:10]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[C:22]([NH2:28])[C:21]=2[CH3:31])=[N:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)n1nc(-c2c(C)cc(C)c([N+](=O)[O-])c2C)n2nc(C(C)(C)C)cc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)n1nc(-c2c(C)cc(C)c(N)c2C)n2nc(C(C)(C)C)cc12
Yield: 92.5 %

Procedure:
Acetic acid (0.5 ml) was added to Raney nickel (8 spoon-spatulas full) and after washing with THF the catalyst was added to the product of part (a) (16.6 g, 44.9 mmole) in THF (160 ml). The resulting mixture was shaken in an atmosphere of hydrogen at atmospheric pressure for 4 hours and then filtered, the catalyst washed with THF and the filtrate evaporated to give a solid (14.1 g). This material was chromatographed on a dry deactivated silica gel column eluting with 1% ethyl acetate in methylene chloride to give the partially hydrated product, m.p. 206°-207° C., 12.7 g (83%).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:37]=[CH:36][C:28]([CH2:29][C:30]2[CH:31]=[C:32]([NH2:35])[NH:33][N:34]=2)=[CH:27][CH:26]=1>O1CCCC1>[CH3:38][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:37]=[CH:36][C:28]([CH2:29][C:30]2[CH:31]=[C:32]([NH:35][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[NH:33][N:34]=2)=[CH:27][CH:26]=1
Reactant: CN(C)CCCOc1ccc(Cc2cc(N)[nH]n2)cc1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(Cc2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)cc1

Procedure:
The named compound is prepared by substituting 5-[4-(3-dimethylamino-propoxy)-benzyl]-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.0351 gms.) is reacted with 0.0881 gms. of 5-[4-(3-dimethylamino-propoxy)-benzyl]-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([OH:26])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([O:26][CH3:1])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC(=O)CC1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.90 g potassium carbonate and 1.30 ml methyl iodide are added to 4.65 g 1-tert.-butoxycarbonylamino-4-oxo-cyclohexanecarboxylic acid in 45 ml N,N-dimethylformamide and the reaction mixture is stirred for three hours at ambient temperature. Then the solvent is distilled off using the rotary evaporator and the residue is divided between 10% potassium carbonate solution and diethyl ether. The aqueous phase is separated off and extracted with diethyl ether and the combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. A colourless oil is left, which slowly crystallises.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH:10]([S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH2:11]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:11]=[CH:10][S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Product: C=CS(=O)(=O)C=CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Fifty grams of 4-chlorophenylsulfenyl chloride was added slowly to 33.0 g of divinyl sulfone in 150 ml of dichloromethane with cooling to remove the heat of reaction. After a few hours of standing at ambient temperature, the solvent was stripped and the crude adduct was dissolved in 200 ml of benzene. Thirty-one g of triethylamine was added slowly with cooling to maintain ambient temperature. After standing for one hour, the triethylamine hydrochloride was removed by filtration. After washing with water and drying over magnesium sulfate, the solvent was stripped to give 64 g of crude product. This was purified by chromatography over silica gel to give 48 g of vinyl 2-(4-chlorophenylthio)vinyl sulfone; calculated for C10HgCl02S2 :S, 24.6; found: S, 24.4.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.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>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)cc2s1
Reactant: OB(O)Oc1ccc(Cl)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: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(-c3ccc(Cl)cc3)cc2s1
Yield: 18 %

Procedure:
Similar to the synthesis of 1-(6-(4-pyrrazolyl)-2-benzothiazolyl)-3-ethylurea, a mixture of 1-(6-bromo-2-benzothiazolyl)-3-ethylurea, 4-chlorophenylboric acid, sodium bicarbonate, and Pd(PPh3)4 in DMF/water mixed solvent (5/1) was reacted to give the desired compound 0.020 g (18%). LC/MS 330 (M−1); LC retention time 2.70 min.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])OC(C)(C)C)([CH3:4])([CH3:3])[CH3:2].Br[CH2:25][CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[CH2:8][N:9]([CH2:25][CH2:26][CH2:27][Cl:28])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)Oc1ccccc1CN(CCCCl)CCNC(=O)C(C)(C)C
Reaction time: 48 h
Yield: 55 %

Procedure:
Compound 14 (1 g, 4.1 mmol), 1-bromo-3-chloropropane (9.7 g, 60 mmol) and K2CO3 (0.56 g, 4.09 mmol) were added to 50 mL CH3CN, and the solution was stirred for 48 h. The solvent was evaporated to dryness and the residue was purified on a silica gel TLC plate that was developed in 2% methanolic NH3 (7 M NH3 in methanol/98% CH2Cl2 yield the desired product as a pale yellow oil (55%). 1H NMR (CDCl3) δ 7.341 (d, 1H, Ar), 7.139 (dd, 1H, Ar), 7.029 (m, 1H, Ar), 6.995 (m, 1H, Ar), 3.592 (s, 2H, —CH2—), 3.539 (t, 2H, —CH2—), 3.167 (m, 2H, —CH2—), 2.583 (ddd, 2H, —CH2—), 2.519 (ddd, 2H, —CH2—), 1.900 (p, 2H, —CH2—), 1.425 (s, 9H, —C(CH3)3), 1.385 (s, 9H, —C(CH3)3). Mass Spec.=399.96 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:1][C:2]2[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (15 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (4.0 g) and triethylamine (1.5 ml), and 4-chlorobenzoyl chloride (2.5 g) was gradually added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[NH:7]1.O.[OH-].[Na+].Cl>CO>[CH2:5]1[CH:6]2[N:7]([C:8](=[O:11])[CH2:9][CH2:10]2)[C:3](=[O:12])[CH2:4]1
Reactant: COC(=O)CCC1CCC(=O)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CCC2CCC(=O)N12

Procedure:
A solution of 136 g of gamma-nitropimelic acid dimethyl ester in 500 ml of methanol is hydrogenated at approximately 3780 psi using 15 g of Raney Nickel as catalyst. The resulting slurry is filtered to remove the catalyst and the filtrate is concentrated at reduced pressure to yield crude 5-oxo-2-pyrrolidinepropanoic acid methyl ester. The 5-oxo-2-pyrrolidinepropanoic acid methyl ester is dissolved in 100 ml of methanol and 100 ml of water and is treated with 94 g of 50% sodium hydroxide solution. The reaction mixture is stirred and is heated to 98° C. with distillation of methanol. The solution is cooled, neutralized with 151 ml of concentrated hydrochloric acid and concentrated at reduced pressure. The residue containing 5-oxo-2-pyrrolidinepropanoic acid is heated at 98°-100° C. for 24 hours with 200 ml of acetic anhydride. The sodium chloride is removed by filtration after the acetic anhydride reaction. The filtrate is then concentrated at reduced pressure and 200 ml of toluene is added and concentration is repeated. The dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione crystallizes and is isolated by filtration. The product is best purified by sublimation at 100° C. and 0.1 mm Hg or by recrystallization from ethanol to give melting point of 179°-182° C.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH2:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40])(OCC)=O>O.C(#N)C>[C:31]1(=[O:40])[N:17]([CH:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH2:7][C:6]([O:5][CH2:2][CH2:3][CH3:4])=[O:18])[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCOC(=O)CC(N)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid propyl ester hydrochloride (1.50 g, 5.52 mmol) and sodium carbonate (0.59g, 5.52 mmol) in 50 mL of water was added N-carboethoxy-phthalimide (1.21 g, 5.52 mmol) in 12 mL of acetonitrile. The reaction was complete in one hour. The acetonitrile was removed in vacuo and 5 mL of ether was added to the mixture, which was stirred overnight at room temperature. The resulting slurry was filtered and the solid was washed with 60 mL of water. The solid was dried in vacuo (24° C., <1 mm) to afford 1.69 g (83.2%) of propyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder: mp 51.2°-52.8° C.; 1H NMR (DMSO-d6 250 MHz) δ7.86 (m, 4H), 6.92-7.33 (m, 4H), 5.66 (dd, 1H, J1=7.5, 2.5 Hz), 3.90 (t, 2H, J=5 Hz), 3.72 (S, 3H), 3.3-3.63 (m, 2H), 1.42 (hex, 2H, J=7.5 Hz), 0.75 (t, 3H, J=7.5 Hz); 13C (DMSO-d6 ) δ 170.2, 167.5, 158.7, 134.7, 131.0, 130.5, 128.3, 123.2, 113.9, 65.6; 55.0, 49.5, 21.3, 9.98. Anal. Calcd for C19H17NO5 :=C, 68.65; H, 5.76; N, 3.81; Found=C, 68.42; H, 5.49; N, 3.76.
Reaction SMILES: [CH2:1]([N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](Cl)=[O:26].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH2:1]([N:4]1[C:9]2[CH:10]=[C:11]([C:25](=[O:26])[CH2:24][C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[Cl:15])[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)COc2ccccc21
Reactant: COc1ccc(CC(=O)Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: C=CCN1C(=O)COc2ccc(C(=O)Cc3ccc(OC)cc3Cl)cc21

Procedure:
In analogy to Example 56, step 1, 4-allyl-4H-benzo[1,4]oxazin-3-one (18.8 g) was reacted with (2-chloro-4-methoxy-phenyl)-acetyl chloride and AlCl3 in 1,2-dichloroethane 3 h at 0° C. The crude product was purified by column chromatography (silica gel, heptane/AcOEt 6:1) to give the title compound (10.6 g) as a white solid. MS (m/e)=372.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[C:8]1[CH:14]=[C:15]([O:22][CH2:23][C@@H:24]([N:29]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:7]2=1.O.NN>CCO>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:15]1[C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:7]2[C:6]3[C:11](=[C:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[C:10](=[O:12])[N:9]([CH3:13])[C:8]=2[CH:14]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)c(C(F)(F)F)cc21
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nccc2c1c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)c(C(F)(F)F)cc21
Temperature: 45 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a solution of (S)-2-(1-((4,6-dimethyl-5-oxo-9-(trifluoromethyl)-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (50 mg, 0.019 mmol) in EtOH (4 mL) was added hydrazine hydrate (6.52 mg, 0.130 mmol). The reaction mixture was allowed to stir at 45° C. for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Symmetry C-18 column (19.0×250 mm) 7.0 micron; mobile phase A: Ammonium acetate in water; mobile phase B: acetonitrile; flow rate: 16.0 mL) to afford the (S)-8-((2-amino-4-methylpentyl)oxy)-4,6-dimethyl-9 (trifluoromethyl)benzo[c][2,7]naphthyridin-5(6H)-one (5 mg, 0.012 mmol, 64% yield) as an off-white solid. LC/MS (ESI) m/e 408.2 [(M+H)+, calcd for C21H25F3N3O2 408.2] LC/MS retention time (method B): tR=1.25 min. HPLC retention time (method A): tR=10.10 min HPLC retention time (method B): tR=10.69 min; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.66 (s, 1H), 8.63 (d, J=5.6 Hz, 1H), 8.22 (d, J=5.6 Hz, 1H), 7.19 (s, 1H), 4.42-4.38 (m, 1H), 4.28-4.20 (m, 1H), 3.83 (s, 3H), 3.58-3.49 (m, 1H), 3.11 (s, 3H), 1.90-1.82 (m, 1H), 1.68-1.62 (m, 1H), 1.58-1.53 (m, 1H), 1.10-1.00 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:35](=[O:36])[O:12][N:11]=[C:10]2[C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:22])[CH3:23])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 70 °C
Yield: 99.2 %

Procedure:
Into a round bottom flask was added N-(3-chloro-4-fluorophenyl)-N′-hydroxy-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboximidamide (85.0 mg, 0.185 mmol), anhydrous THF (1.1 mL), and N,N-carbonyldiimidazole (55 mg, 0.34 mmol). The reaction was heated to 70° C. for 2.5 h. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (89 mg, 99%). MF═C20H26ClFN4O3SSi; LCMS calculated for C20H27ClFN4O3SSi (M+H)+: m/z=485.2.