Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: CN1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 51 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-methylpiperidone (0.72 g, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 26 hours. During this time extra portions of N-methylpiperidone (0.5 mL, 0.75 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq) were added. A saturated aqueous solution of NaHCO3 was then added and the reaction mixture was concentrated under reduced pressure. 10% ammonium hydroxide was added until pH 10 and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. After purification by chromatography over silica gel (DCM/MeOH/NH3 7% in MeOH 90:8:2) 1.025 g of title compound were obtained as off-white solid (51% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc2c1NCC2
Solvent: CC#N
Product: Fc1cc(Br)cc2c1NCC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.7 %

Procedure:
7-Fluoroindoline (1.1 g, 8.0 mmol) was dissolved in acetonitrile (80 mL), cooled to 0° C., and N-bromosuccinimide (1.43 g, 8.0 mmol) was added. The mixture was warmed to 25° C. and stirred for 3 hours. The mixture was concentrated to 10 mL and diluted with ethyl acetate and washed with NaHCO3, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-15% ethyl acetate in hexane) afforded 5-bromo-7-fluoroindoline (1.05 g). MS (ES) m/z 215.8; HPLC purity 97.6% at 210-370 nm, 10.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][C:53]1[CH:54]=[N:55][C:56]2[C:61]([CH:62]=1)=[CH:60][CH:59]=[CH:58][CH:57]=2.C(N(CC)CC)C>CN(C=O)C>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([NH:52][C:53]4[CH:54]=[N:55][C:56]5[C:61]([CH:62]=4)=[CH:60][CH:59]=[CH:58][CH:57]=5)=[O:18])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Reactant: Nc1cnc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2ccccc2c1)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 75 mg, 0.31 mmol) and PyBOP (175 mg, 0.34 mmol) in DMF (2 mL) is stirred for 30 min. 3-Aminoquinoline (49 mg, 0.34 mmol) and triethylamine (171 μL, 1.22 mmol) are added and the reaction is stirred at room temperature for 16 h. The mixture is purified via preparative HPLC using a gradient elution from 10-75% acetonitrile/H2O with 0.1% TFA to afford the title compound (93 mg, 82%). LCMS: 372.20 (M+H+). (Method V)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]#[N:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:13]1[CH2:18][CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15][CH2:14]1
Reactant: CCS(=O)(=O)Cl
Reactant: N#Cc1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 42.4 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carbonitrile (Intermediate 9) (0.222 g, 0.493 mmol) was suspended in dichloromethane (5 mL) and treated with diisopropylethyl amine (0.257 mL, 1.48 mmols), and ethane sulfonyl chloride (0.070 mL, 0.74 mmols) at ambient temperature. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.083 g, 24%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[S:17][CH:18]=[C:19]([C:21]([NH:23][C:24]2[C:25]([N:33]3[CH2:38][CH2:37][CH2:36][C@H:35]([NH:39]C(=O)OC(C)(C)C)[CH2:34]3)=[C:26]3[CH:32]=[CH:31][S:30][C:27]3=[N:28][CH:29]=2)=[O:22])[N:20]=1>C(Cl)Cl>[NH2:39][C@H:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:25]2[C:24]([NH:23][C:21]([C:19]3[N:20]=[C:16]([C:10]4[C:9]([F:8])=[CH:14][CH:13]=[CH:12][C:11]=4[F:15])[S:17][CH:18]=3)=[O:22])=[CH:29][N:28]=[C:27]3[S:30][CH:31]=[CH:32][C:26]=23)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (118.2 mg, 0.2068 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (33.5 mg, 34%). LCMS calc. for C22H20F2N5OS2 (M+H)+: m/z=472.1. found 472.1.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([NH:38][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1>>[C:39]([NH:38][C:34]1[CH:33]=[C:32]([CH:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][NH:22][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:27][CH2:28]2)[CH:37]=[CH:36][CH:35]=1)(=[O:43])[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CCCCCC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CCCCCC(C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)(c1ccccc1)c1ccccc1

Procedure:
Example 11 was prepared from 2,2-diphenylheptanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.45 (s, 1H), 7.40 (m, 1H), 7.37–7.19 (m, 11H), 6.88 (d, 1H, J=7.3 Hz), 6.34 (t, 1H, J=4.5 Hz), 3.34–3.27 (m, 3H), 2.94–2.87 (m, 2H), 2.52 (septet, 1H, J=6.9 Hz), 2.46–2.34 (m, 4H), 2.27 (t, 2H, J=6.9 Hz), 2.00–1.91 (m, 2H), 1.77–1.69 (m, 2H), 1.69–1.52, (m, 5H), 1.30–1.20 (m, 12H); ESMS m/e: 568.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][C:5]2[N:9]=[C:8]([SH:10])[NH:7][C:6]=2[CH:11]=1.Cl.[CH3:20][C:21]1[C:22]([CH2:27]Cl)=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C>[CH3:20][C:21]1[C:22]([CH2:27][S:10][C:8]2[NH:7][C:6]3[CH:11]=[C:2]([F:1])[C:3]([N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:4][C:5]=3[N:9]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CN1CCN(c2cc3nc(S)[nH]c3cc2F)CC1
Reactant: Cc1cccnc1CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccnc1CSc1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Yield: 21.5 %

Procedure:
The title compound (0.6 g, 22%) was prepared by the general procedure using 6-fluoro-5-(4-methylpiperazin-1-yl)-2-mercapto-1H-benzimidazole (2.0 g, 7.5 mmol) (obtained in preparation 4), 3-methyl-2-chloromethylpyridine hydrochloride (1.0 g, 7.5 mmol), sodium hydroxide (0.36 g, 9.0 mmol) and ethanol (15 mL). IR (Neat) 3150, 1429 cm-1 ; 1H NMR (CDCl3) δ 2.42 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.90 (m, 4H, N(CH2)2), 3.20 (m, 4H, N(CH2)2), 4.38 (s, 2H, SCH2), 7.12 (d, J=7.6 Hz, 1H), 7.20-7.26 (m, 2H), 7.58 (d, J=7.4 Hz, 1H), 8.46 (d, J=4.6 Hz, 1H); Mass (m/z) 371 (M+.).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:26](OCC)=[O:27]>O1CCCC1>[C:24]([C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:26][OH:27])#[N:25]
Reactant: N#CCCCCCc1ccccc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC(=CO)CCCCc1ccccc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A stirred solution of 2.2 mL (0.016 mole) of diisopropylamine in 200 mL of tetrahydrofuran was cooled to -80° C., and 6.4 mL (0.016 mole) of n-butyllithium (2.5 Molar in hexanes) was added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture was stirred for an additional 15 minutes. While still maintaining the reaction mixture temperature at -80° C. to -75° C., a solution of 2.5 grams (0.016 mole) of 6-phenylhexanenitrile in 50 mL of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for an additional 30 minutes. After this time, a solution of 1.3 mL (0.016 mole) of ethyl formate in 50 mL of tetrahydrofuran was added dropwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for two hours at -80° C. to -70° C. The reaction was quenched with 100 mL of water, and the mixture was acidified with 6N hydrochloric acid. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of 2-cyano-6-phenyl-1-hexen-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:21][NH2:22]>C(O)C>[CH3:21][NH:22][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CN
Reactant: COc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ncccc1OC

Procedure:
1-Methylthio-1-[2-((3-methoxy-2-pyridyl)methylthio)ethylamino]-2-nitroethylene (1.4 g) was stirred with a solution of methylamine in ethanol (25 ml, 33% solution) and dissolved within a minute. After a further 3 minutes a crystalline product separated and recrystallisation from ethanol/ether yielded the title product (1.1 g), m.p. 145.5°-147°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:14](=[NH:17])[NH:15][OH:16])([CH3:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[C:19](OC(=O)C)(=O)[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:13])([C:14]1[N:17]=[C:19]([CH3:20])[O:16][N:15]=1)[CH2:9][CH:10]1[CH2:12][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(C(C)(CC2CC2)NC(=O)OC(C)(C)C)no1
Reaction time: 5 h
Yield: 46 %

Procedure:
To a solution of [2-cyclopropyl-1-(N-hydroxycarbamimidoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (300 mg, 1.16 mmol) in acetic anhydride (10 mL) was heated to 100° C. and stirred for 5 hours. After evaporation of solvents, the residue was dissolved in H2O (20 mL) and basified by aqueous NaHCO3 solution (pH˜7-8). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 20 g, eluting with 20% ethyl acetate in petroleum ether) to give the title compound (0.15 g; 46%) as colorless sticky solid. 1H-NMR (DMSO, 400 MHz): 0.012-0.014 (m, 2H); 0.31-0.38 (m, 2H); 0.56-0.58 (m, 1H); 1.32 (s, 9H); 1.55 (s, 3H); 1.69-1.98 (brs, 2H); 2.56 (s, 3H), 7.19 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH3:12])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Brc1ccc(I)cc1
Product: COC(=O)c1ccc(-c2ccc(Br)cc2)c(C)c1
Yield: 23 %

Procedure:
In accordance with Example 19-(2), but using methyl 4-bromo-3-methylbenzoate instead of tert-Butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 1-bromo-4-iodobenzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 23%) was afforded as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[CH2:17]([Mg]Br)[CH3:18].Cl>O1CCCC1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 48.9 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzaldehyde (300 mg, 1.24 mmol) in anhydrous tetrahydrofuran (3 mL) was added with ethylmagnesium bromide (1.00 M solution in anhydrous tetrahydrofuran, 1.86 mL, 1.86 mmol) with stirring on an ice bath, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 M hydrochloric acid on an ice bath (pH<7), and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1-[3,5-bis(trifluoromethyl)phenyl]-1-propanol (165 mg, 49%) as colorless solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:11][CH2:12][CH:13]([O:16][C:19](=[O:20])[CH:18]([F:22])[F:17])[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(O)C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 50.8 %

Procedure:
In 40 ml of dichloromethane were dissolved 3.0 g (13 mmol) of 4-(4-propylcyclohexyl)cyclohexanol, 2.3 g (24 mmol) of difluoroacetic acid, and 0.9 g (9 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 20 ml of solution of 3.1 g (15 mmol) of DCC in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 2.0 g (6.6 mmol) of difluoroacetic acid 4-(4-propylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-propylcyclohexyl)-cyclohexanol was 51%.
Reaction SMILES: Br[CH:2]([C:16](=[O:18])[CH3:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4].[C-:19]#[N:20].[Na+].Cl>CS(C)=O.O>[CH3:17]/[C:16](/[OH:18])=[C:2](/[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:4])\[C:19]#[N:20]
Reactant: CC(=O)C(Br)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 2-bromo-3-oxo-N-[4-(trifluoromethyl)phenyl]butanamide (10 g) [obtained from above step-b] and sodium cyanide (1.69 g) in DMSO (30 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml) and acidified with 50% HCl solution. Precipitated solid was filtered and washed with water. The solid was dried to give Teriflunomide (7.12 g).
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]1[O:25][C:24](=[O:26])[CH:23]=[CH:22]1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([S:9]([C:6]([CH:22]2[CH:21]([O:20][CH3:19])[O:25][C:24](=[O:26])[CH2:23]2)([CH3:8])[CH3:7])(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: COC1C=CC(=O)O1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COC1OC(=O)CC1C(C)(C)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.3 ml of a cyclohexane solution of 1.95M of butyllithium was slowly added with stirring at -70° C. under an inert atmosphere to a mixture of 500 mg of isopropyl-p-tolyl sulfone and 10 ml of anhydrous tetrahydrofuran and the mixture was stirred at -70° C. for 30 minutes. A solution of 287 mg of 5-methoxy-2,5-dihydrofuran-2-one in 4 ml of tetrahydrofuran was added to the mixture over 10 minutes and the mixture was held at -70° C. for one hour and was then poured into aqueous monosodium phosphate solution at 0° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether to obtain 490 mg of trans dl 4-(2-p-toluenesulfonyl-prop-2-yl)-5-methoxy-tetrahydrofuran-2-one in the form of white crystals melting at 129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (5 gm,) was suspended in methanol(40 ml) & water (6 ml) and then added sodium borohydride (0.211 gm.) at 30° C. and the reaction mixture was stirred for 1 hr. To the reaction mixture was added hydrochloric acid (30 ml). Then the reaction mixture was stirred for 2 hours, The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (4.55 gm).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C-:3]=[N:2]1.[Na+].[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1>CN(C)C=O.COC(C)(C)C>[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:21][CH:22]=1
Reactant: [c-]1nc[nH]n1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCn2cncn2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
0.051 g of sodium 1,2,4-triazolide is admixed with a solution of 0.10 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}-ethoxy)piperidine-1-carboxylate in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at 90° C. over 40 minutes. The mixture is cooled to room temperature, diluted with tert-butyl methyl ether and washed with water. The water phase is extracted with tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (2:1 EtOAc-heptane); Rt=5.66.
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=2)[CH2:8][C:7](C(OC)=O)=[C:6]([OH:13])[CH2:5][CH2:4]1)#[N:2].[Na+].[Cl-].O>CS(C)=O>[CH3:20][C:17]1[N:16]=[CH:15][C:14]([C:3]2([C:1]#[N:2])[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8]2)=[CH:19][N:18]=1
Reactant: COC(=O)C1=C(O)CCC(C#N)(c2cnc(C)nc2)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncc(C2(C#N)CCC(=O)CC2)cn1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A solution of methyl 5-cyano-2-hydroxy-5-(2-methylpyrimidin-5-yl)cyclohex-1-enecarboxylate (6.2 g, 0.023 mol), NaCl (1.46 g, 0.025 mol) and H2O (1.24 mL, 0.069 mol) in DMSO (50 mL) was heated to 160° C. for 3 h. After cooling to room temperature, the reaction was added water and extracted with EtOAc (6×100 mL). The organic layer was washed with brine, dried over Na2SO4 and concentracted. The crude product was purified by flash chromatography(EtOAc: Petroluem ether=1:3˜3:2) to give 1-(2-methylpyrimidin-5-yl)-4-oxocyclohexanecarbonitrile (2 g, yield: 41%). 1H NMR (CDCl3 400 MHz): δ8.80 (s, 2H), 3.00-2.90 (m, 2H), 2.77 (s, 3H), 2.70-2.60 (m, 2H), 2.60-2.50 (m, 2H), 2.40-2.25 (m, 1H).