Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9]COC)=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15]COC)[C:4]=1[CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]1[C:30]([O:31][CH2:32]OC)=[C:29]([O:35]C)[CH:28]=[C:27]([O:37][CH2:38]OC)[C:26]=1[O:41]C.Cl.C(=O)([O-])O.[Na+].O=O>O1CCCC1.C(O)(C)C.CO.ClCCl>[CH3:1][O:2][C:3]1[C:8](=[O:9])[CH:7]=[C:6]([O:13][CH3:14])[C:5](=[O:15])[C:4]=1[CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]1[C:26](=[O:41])[C:27]([O:37][CH3:38])=[CH:28][C:29](=[O:35])[C:30]=1[O:31][CH3:32]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCOCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=O
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: COC1=CC(=O)C(OC)=C(CCCOCCC2=C(OC)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
484 Milligrams of 2-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]ethyl 3-[2,5-dimethoxy-3,6bis(methoxymethoxy)phenyl]propyl ether was dissolved in a mixed solvent of 5 ml of tetrahydrofuran with 5 ml of isopropanol, to this solution was added 1.0 ml of solution prepared by dissolving 10% (by weight) of hydrogen chloride in a mixture of tetrahydrofuran with isopropanol (1:1), and the whole mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and benzene was added then further treated under reduced pressure to concentrated. The residue obtained was dissolved in 10 ml of methanol, and a catalytical amount of sodium hydrogen carbonate was added thereto and oxygen gas was blown thereinto. The precipitated crystals were dissolved by adding dichloromethane and filtered. The filtrate was concentrated and the residue obtained was purified by means of a silica gel column chromatography, (diameter 2 cm×length 5 cm, developping solvent: 10% ethyl acetate-dichloromethane solution, adsorbent: "Wakogel C-200", to obtain a crude product, then recrystallized from ethanol to obtain 243 mg of 2-(3,6-dimethoxy1,4-benzoquinon-2-yl)ethyl 3-(3,6-dimethoxy-1,4-benzoquinon2-yl)propyl ether. Yellow needles crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.Br[CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:30][CH2:31][OH:32])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCCO)c(F)c1

Procedure:
In analogy to example 221, step 6, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 2-bromoethanol in N,N-dimethylacetamide in the presence of cesium carbonate to give the title compound as a colourless foam, MS (ESI+): m/z=444.2 [M+H]+.
Reaction SMILES: O.S(=O)(=O)(O)O.[OH:7][C:8]([CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C#N>C(O)(=O)C>[C:12]1([CH2:9][C:8]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:7])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CC(=C(O)C1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(Cc1ccccc1)C1CCN(Cc2ccccc2)CC1
Yield: 96.3 %

Procedure:
To 200 parts of water were added carefully 200 parts of acetic acid while stirring and cooling. Then there were added dropwise (slowly) 368 parts of sulfuric acid. 90 Parts of α-[hydroxy[1-(phenylmethyl)-4-piperidinyl]methylidene]benzeneacetonitrile were added and the whole was stirred and refluxed overnight. The acetic acid was evaporated and the residue was poured into crushed ice. The mixture was alkalized with concentrate ammonium hydroxide and the oily product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 79 parts (96.3%) of 2-phenyl-1-[1-(phenylmethyl)-4-piperidinyl]ethanone as a residue (intermediate 6).
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].C(Cl)Cl.F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.O>[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([N:42]=[C:5]2[N:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:3](=[O:15])[C:2]([CH3:1])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:6]2)=[CH:40][CH:39]=1
Reactant: CC1(c2ccccc2)SC(=S)N(Nc2ccccc2)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(c2ccccc2)SC(=Nc2ccc(Cl)cc2)N(Nc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.8 %

Procedure:
5-Methyl-5-phenyl-3-phenylamino-2-thioxothiazolidin-4-one (0.28 g) was mixed with a 1M methylene chloride solution of triethyloxonium tetrafluoroborate (1 ml) at room temperature. The reaction mixture was stirred for 24 hrs at room temperature then p-chloroaniline (0.25 g) in chloroform (10 ml) was added to the mixture at 0° C. The mixture was stirred at room temperature for 1 hr and then water was added. The separated oil was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform-n-hexane, 1/1) to yield 2-(4-chlorophenyl)imino-5-methyl-5-phenyl-3-phenylaminothiazolidin-4-one (0.21 g) having a melting point of 53-54° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([C:19]([C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=4)=O)[C:9]3=O)=[CH:4][C:3]1=2.[CH3:32][NH:33][NH2:34]>CO>[CH3:32][N:33]1[C:9]2[C:10]3[C:5]([CH2:6][CH2:7][C:8]=2[C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:34]1)=[CH:4][C:3]1[C:2]([CH3:1])([CH3:31])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=1[CH:11]=3
Reactant: CNN
Reactant: COC(=O)c1ccc(C(=O)C2CCc3cc4c(cc3C2=O)C(C)(C)CCC4(C)C)cc1
Solvent: CO
Product: COC(=O)c1ccc(-c2nn(C)c3c2CCc2cc4c(cc2-3)C(C)(C)CCC4(C)C)cc1
Yield: 65.1 %

Procedure:
4.5 g of methyl 4-(3,4,5,6,7,8-hexahydro-5,5,8,8-tetramethyl-1(2H)-anthracenon-2-ylcarbonyl)benzoate was suspended in 100 ml of methanol, followed by the addition thereto of 0.64 g of monomethylhydrazine. The obtained mixture was heated under reflux for 2 hours and cooled by allowing to stand to precipitate a solid. This solid was recovered by filtration and washed with methanol. 3.0 g of the title compound was obtained as a pale-yellow solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:19]3/[C:20](=[O:28])[NH:21][C:22]4[C:27]/3=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:15][CH:16]=2)[CH:11]=[N:10]1>CN(C=O)C>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([C@H:18]3[C@@:19]4([C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][C:20]4=[O:28])[CH2:2]3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of trimethylsulfoxonium iodide (33 mg, 0.15 mmol) in anhydrous DMF (1 mL) was added sodium hydride (60% dispersion in oil) (16 mg, 0.4 mmol) at 0° C. The mixture was stirred for 15 min after which time (E)-3-((1H-indazol-5-yl)methylene)indolin-2-one (26 mg, 0.1 mmol) was added. The solution was stirred overnight at rt. The reaction was quenched with sat. NH4Cl solution (2 mL), extracted with EtOAc (50 mL), dried over MgSO4 and concentrated to dryness. The title was compound isolated by preparative HPLC) as a white solid (5 mg, 18%). 1H NMR (400 MHz, d6-DMSO) δ 13.03 (s, 1H), 10.58 (d, 1H, J=8.3 Hz), 8.02 (s, 1H), 7.74 (s, 1H), 7.40 (d, 1H, J=8.9 Hz), 7.11 (d, 1H, J=8.6 Hz), 6.98 (t, 1H, J=7.7 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.50 (t, 1H, J=7.3 Hz), 5.94 (d, 1H, 7.5 Hz), 3.17-3.13 (m, 1H), 2.27-2.23 (m, 1H), 1.98-1.95 (m, 1H); MS ESI 276.1 [M+H]+, calcd for [C17H13N30+H]+ 276.3.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31].[BH3-]C#N.[Na+].[OH-].[Na+]>CC(O)=O.CO.ClCCl>[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][NH:22][C:20](=[O:21])[CH2:19][NH:18][C:16]([O:15][CH2:14][CH:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:17])[CH2:25][CH2:26]2)=[CH:34][CH:33]=1)[CH3:31]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: CCc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1ccc(CN2CCC(CNC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 62.1 %

Procedure:
To A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.00 g, 2.33 mmol) in 2.5% AcOH/CH3OH (80 mL) were added 4-ethylbenzaldehyde (1.09 g, 8.16 mmol) and NaBH3CN (6.59 g, 10.5 mmol). The reaction mixture was stirred at 60° C. for 13 h. After the mixture was cooled to room temperature, 1 N aqueous NaOH solution (50 mL) and dichloromethane (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (SiO2, CH3OH/AcOEt 2:8) afforded 1-(4-ethylbenzyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (740 mg, 62%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@H:6]([OH:11])[C:7](=O)[CH2:8][OH:9].CN(B)C.C(N(CC)CC)C>O>[NH:2]1[C@H:7]([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[CH2:3]1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: BN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C

Procedure:
50 g (0.23 mol) of 6-amino-6-desoxy-L-sorbose hydrochloride were dissolved in 500 ml of distilled water, and the solution was added in the course of one hour to a solution of 11.2 g of dimethylaminoborane in 500 ml of distilled water, whilst stirring at a temperature of 50° C. The mixture was stirred for one hour at room temperature and one hour at 50° C., 5 ml of triethylamine were added to it, and it was then poured over a column containing 800 ml of strongly basic ion exchanger ("Lewatit" MP 500 OH- -form). The exchanger was washed with distilled water, and the runnings collected were concentrated to a syrup on a rotary evaporator. The concentrated syrup was crystallised at 50° C., with addition of a large amount of ethanol. The suspension of crystals was cooled and filtered off under suction, and the crystalline product was dried in a vacuum drying cabinet.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:25](O)=[O:26])([CH3:24])[CH3:23])[CH:16]=1)[C:11]([CH3:29])([CH3:28])[CH2:10]2)=[O:4].Cl.[CH3:32][N:33](C)CCCN=C=NCC.CN.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:30])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([CH3:24])([C:25](=[O:26])[NH:33][CH3:32])[CH3:23])[CH:16]=1)[C:11]([CH3:28])([CH3:29])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)C(C)(C)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3c(cc(Cl)cc3C(=O)OC)CC2(C)C)c1
Reaction time: 48 h
Yield: 99.4 %

Procedure:
A mixture of 2-[3-(1-carboxy-1-methyl-ethylamino)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (73 mg, 0.17 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 4-dimethylaminopyridine (41.5 mg, 0.34 mmol), methaneamine (0.26 mL, 0.52 mmol) in tetrahydrofuran and triethylamine (34 mg, 0.34 mmol) in dichloromethane (10 mL) was stirred for 48 hours. Removal of the solvent to afford the crude product 6-chloro-3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (75 mg, 100%) which was used in next step without purification: LC/MS m/e calcd for C24H30ClN3O3 (M+H)+: 444.98, observed: 444.1.
Reaction SMILES: C[C:2]1[C:3]([N:11]=[C:12]=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[O:10].[C:14]1(N=C=O)C=CC(N=C=O)=CC=1.[N-]=C=O.[N-]=C=O.C1(CC2C=CC=CC=2)C=CC=CC=1.C1(N=C=O)C=CC=C(N=C=O)C=1.C(N=C=O)CCCCCN=C=O.C(N=C=O)CCCN=C=O.COC1C=C(C2C=CC(N=C=O)=C(OC)C=2)C=CC=1N=C=O.C1C=C(N=C=O)C2C=CC=C(N=C=O)C=2C=1.C1(CN=C=O)C=CC(CN=C=O)=CC=1.C1(CN=C=O)C=CC=C(CN=C=O)C=1.N(CC1CCCC(CN=C=O)C1)=C=O.N(CC1CCC(CN=C=O)CC1)=C=O.C1C(CC2CCC(N=C=O)CC2)CCC(N=C=O)C1.O=C=NC1CC(C)(C)CC(C)(CN=C=O)C1>>[CH3:14][C:4]1[C:3]([N:11]=[C:12]=[O:13])=[CH:2][C:7]([N:8]=[C:9]=[O:10])=[CH:6][CH:5]=1
Reactant: Cc1c(N=C=O)cccc1N=C=O
Reactant: O=C=Nc1ccc(N=C=O)cc1
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: COc1cc(-c2ccc(N=C=O)c(OC)c2)ccc1N=C=O
Agent: O=C=NC1CCC(CC2CCC(N=C=O)CC2)CC1
Solvent: c1ccc(Cc2ccccc2)cc1
Product: Cc1ccc(N=C=O)cc1N=C=O

Procedure:
2,6-tolylene diisocyanate; p-phenylene diisocyanate; diphenylmethane diisocyanate (may be abbreviated as "MDI"); m-phenylene diisocyanate; hexamethylene diisocyanate; tetramethylene diisocyanate; 3,3'-dimethoxy-4,4'-biphenylene diisocyanate; 2,4-naphthalene diisocyanate; 3,3'-dimethyl-4,4-biphenylene diisocyanate; 4,4'-diphenylene diisocyanate; 4,4'-diisocyanato diphenyl ether; 1,5-naphthalene diisocyanate; p-xylylene diisocyanate; m-xylylene diisocyanate; 1,3-diisocyanato methylcyclohexane; 1,4-diisocyanato methylcyclohexane; 4,4'-diisocyanato dicyclohexane; 4,4'-diisocyanato dicyclohexylmethane; and isophorone diisocyanate.
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].[Si:5](Cl)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].N1C=CN=C1>C(Cl)(Cl)Cl>[Si:5]([O:4][CH2:3][CH2:2][I:1])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OCCI
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCI
Yield: 99.9 %

Procedure:
A mixture of 2-iodoethanol (12.4 g, 72 mmol) and tert-butyldimethylsilyl chloride (11.94 g, 79 mmol) in chloroform (10 ml) was treated with imidazole (5.39 g, 79 mmol) which produced a white suspension. This was filtered and washed with chloroform. The filtrate was evaporated under reduced pressure to give the product as a colourless liquid (20.592 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])=[CH:4][S:5][CH:6]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1>[Cl:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[C:4]([C:21]([OH:23])=[O:22])[S:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1cscc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1scc(Cl)c1C(=O)Nc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Chlorothiophene-3-carboxanilide (14.6 g, 0.061 mol) is dissolved in 450 ml of THF and the solution is cooled to -70° C.; n-butyllithium (0.13 mol, 1.6N solution in n-hexane) is then added. After 30 minutes, carbon dioxide is gassed in until the solution was saturated, and the solution is allowed to heat up slowly to room temperature. It is then concentrated to dryness, the solid residue is taken up in a mixture of water, sodium hydroxide solution and ethyl acetate, the phases are separated and the aqueous phase is acidified with hydrochloric acid, thus precipitating the carboxylic acid. Yield: 13.5 g, 78%; m.p. 208°-210° C. (active ingredient no. 2.008).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:1][C:2]2[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH3:16])[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (6.00 g, 25.7 mmol) in CH2Cl2 (120 mL) and AcOH (6 mL) was added N-Boc piperidinone (6.70 g, 33.4 mmol) and sodium triacetoxyborohydride (13.6 g, 64.3 mmol). The reaction mixture was stirred at 23° C. for 20 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/EtOAc=4/1) to give the titled compound (10.6 g, 98% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.37 (s, 1H), 6.88 (s, 1H), 4.05 (m, 2H), 3.90 (s, 3H), 3.01 (m, 3H), 2.32 (s, 3H), 1.71 (m, 2H), 1.48-1.61 (m, 2H), 1.45 (s, 9H); MS (ES) [M−H] 415.1.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6].[H][H]>CO.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:20][CH3:21])=[C:14]([NH2:17])[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CCN(C)C)CCC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N)N(C(=O)CCN(C)C)CCC2
Yield: 95.1 %

Procedure:
N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-3-oxo-1-propanamine (crude from previous reaction, assumed 0.91 mmol) was dissolved in methanol (10 mL), treated with 10% palladium on carbon (50 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 1-[3-(dimethylamino)propanoyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.24 g, 93% over three steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.74-1.85 (m, 2 H), 2.09 (bs, 6 H), 2.51-2.60 (m, some signals may be underneath DMSO, 6 H), 3.58 (t, J=6.4 Hz, 2 H), 3.74 (s, 3 H), 4.60 (bs, 2 H), 6.60 (s, broadening due to amide rotomers, 2 H); ESIMS (M+H)+=278.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]#[N:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15]1(B(O)O)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:2]([CH:15]2[CH2:17][CH2:16]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])#[N:14]
Reactant: COC(=O)c1cc(C#N)c(C)cc1Br
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C#N)c(C)cc1C1CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of methyl 2-bromo-5-cyano-4-methylbenzoate (compound 190.2, 600 mg, 2.13 mmol, 1.00 equiv, 90%) in toluene (20 mL) under nitrogen were added cyclopropylboronic acid (552 mg, 6.43 mmol, 2.00 equiv), a solution of potassium carbonate (876 mg, 6.34 mmol, 2.00 equiv) in water (1 mL), Pd(dppf)Cl2 (252 mg, 0.10 equiv), and Pd(OAc)2 (70 mg, 0.10 equiv). The resulting mixture was stirred under nitrogen at 100° C. overnight. After cooling to ambient temperature, the mixture was diluted with 20 mL of H2O, then extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to furnish 450 mg (89%) of methyl 5-cyano-2-cyclopropyl-4-methylbenzoate as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][NH:10][CH2:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C@H:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([OH:28])=O)=[CH:22][CH:21]=1)[CH3:16].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:11][CH3:12])[C:26](=[O:28])[CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([O:17][CH2:15][CH3:16])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383 g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.706 g, 2.20 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (40 mL) and the organic phase was washed with 5% HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methylene chloride/ethyl acetate 10:1 as the eluent yielded 0.54 g (58%) of a colourless oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.37 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as an off-white solid (0.17 g, 34%). MS (ISP) 507.2 [(M+H)+]; mp 233.5° C.