Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2C=CC=CC=2N=C1NN=CC1OC([N+]([O-])=O)=CC=1.[N+:21]([C:24]1[S:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22].[NH:31]([C:33]1[S:34][C:35]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:36]=2[N:37]=1)[NH2:32]>>[F:45][C:42]([F:43])([F:44])[C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([NH:31][N:32]=[CH:29][C:27]3[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=3)[S:34][C:35]=2[CH:41]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: NNc1nc2ccc(C(F)(F)F)cc2s1
Agent: O=[N+]([O-])c1ccc(C=NNc2nc3ccccc3s2)o1
Product: O=[N+]([O-])c1ccc(C=NNc2nc3ccc(C(F)(F)F)cc3s2)s1

Procedure:
The compound 3h was prepared according procedure described for 3a by employing 5-nitrothiophen aldehyde (157 mg, 1 mmol) and 2-hydrazino-6-trifluoromethyl-benzothiazole (233 mg, 1 mmol) at 70° C. for 2 h (yield 312 mg, 84%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: CCN
Product: CCNC(=O)c1ccccc1-c1ccccc1
Yield: 94 %

Procedure:
2-Phenylbenzoic acid was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with 70% aq ethylamine using General Method E1 to afford 10.59 g of N-ethyl-2-phenylbenzamide in 94% yield. m.p. 77°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.CN(C)C(=O)C>CCOC(C)=O.O>[Br:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: O=C(O)C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cc(Br)cc(N2CCC(C(=O)O)CC2)c1
Temperature: 130 °C

Procedure:
A mixture of 3-bromo-5-fluorobenzonitrile (1.6 g, 7.8 mmol), piperidine-4-carboxylic acid (2.6 g, 12.0 mmol), triethylamine (4.0 mL, 28.5 mmol) and N,N-dimethylacetamide (1.5 mL) in a sealed tube was heated to 130° C. for 48 hr. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated to give a crude reside which was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[N:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[N:32][CH:33]=3)[NH:26][CH:27]=2)[CH:19]=[CH:20][C:21]=1[Cl:22].C(O)(=O)C.[CH:44](=O)[CH:45]([CH3:47])[CH3:46]>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[NH:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([N:34]4[CH2:39][CH2:38][N:37]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH2:36][CH2:35]4)=[N:32][CH:33]=3)=[N:26][CH:27]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CC(C)C=O
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)CN1CCN(c2ccc(-c3ncc(-c4ccc(Cl)c(Cl)c4)[nH]3)cn2)CC1

Procedure:
Sodium triacetoxyborohydride (20.2 g) was added to a suspension of 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (23.8 g), acetic acid (5.1 mL), and isobutyraldehyde (6.35 mL) in THF (250 mL). The resultant suspension was stirred at ambient temperature for 18 hours, and then the reaction mixture was diluted with 1 N NaOH (1000 mL) and ethyl acetate (450 mL). The layers were separated, and the organic phase was diluted with hexanes (1000 mL). The resultant precipitate was collected by filtration, and the mother liquors were concentrated to 400 mL. The second crop of precipitate was collected and combined with the first crop to provide 1-{5-[5(3,4,-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isobutyl-piperazine (22.5 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[CH2:1]([NH:8][C:9](=[O:18])[NH:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([NH:19][C@@H:20]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[CH:46][CH:45]=1)[C:21]([N:23]([CH2:35][CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: CC(C)(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)(C)NC(=O)NCc1ccccc1)OCC
Yield: 88.6 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 3-(3-benzylureido)-3-methylbutanoic acid (Compound VI-2) (170 mg, 0.68 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (223 mg, 0.45 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethylacetate=50:50 to 0:100) to obtain the title compound (289 mg, 89%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2].[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([O-])(O)=O.[Na+].[Li+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH:1]([C:3]1[CH:8]=[C:7]([CH:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=[C:5]([CH:10]=[O:11])[C:4]=1[OH:12])=[O:2]
Reactant: O=Cc1cc(Br)cc(C=O)c1O
Reactant: C=CCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCCCCCCCC=Cc1cc(C=O)c(O)c(C=O)c1
Temperature: 82 °C
Reaction time: 40 h
Yield: 50.6 %

Procedure:
2,6-Diformyl-4-bromophenol (1.00 g, 4.37 mmol), 1-dodecene (4.8 mL, 21.7 mmol), 1.40 g tetrabutylammonium bromide (4.34 mmol), 0.50 g NaHCO3 (5.95 mmol), 1.00 g LiCl (23.6 mmol) and 0.100 g palladium diacetate (Pd(OAc)2) (0.45 mmol) were combined in 30 mL degassed anhydrous dimethylformamide (DMF). The mixture was sparged with argon for 10 min and then sealed in a pressure vial which was warmed to 82° C. and held for 40 h. The crude reaction mixture was partitioned between CH2Cl2 and 0.1 M HCl solution. The organic layer was washed with 0.1 M HCl (2×), brine (2×), and saturated aqueous NaHCO3 (2×), dried over MgSO4 and concentrated under reduced pressure. The dark yellow oil was purified by column chromatography on silica gel (25% hexanes in Et2O) to give 0.700 g (51%) of the title compound as primarily the Z isomer.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].BrCC1(CC(OC)=O)CC1>ClCCl.O>[CH3:18][S:19]([O:1][CH2:2][C:3]1([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC1(CO)CC1
Agent: COC(=O)CC1(CBr)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: 0 °C

Procedure:
8.45 g of crude methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (compound 14a) was dissolved in 85 ml dry dichloromethane. The pale yellow solution was cooled to 0° C. Then, 7.71 g triethylamine was added and 8.05 g methanesulfonyl chloride was added dropwise over 8 minutes. The yellow suspension was stirred at 0° C. TLC showed that after 10 minutes the reaction was completed. To the reaction mixture, 35 ml water and 20 ml dichloromethane were added. The water layer was washed with 20 ml dichloromethane. The combined organic layers were washed with 30 ml water, dried (Na2SO4) and evaporated to dryness, resulting in a yellow oil. The product was immediately used in the next step (synthesis of methyl 1-(bromomethyl)-cyclopropaneacetate).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[CH:15])[CH:8]=2)[S:3]1.I[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]#[C:15][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH:8]=2)[S:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)S2
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)S3)cc1
Reaction time: 40 h

Procedure:
A solution of 110.7 mg (o.481 mmol) of 2,2,4,4-tetramethyl-6-ethynylthiochroman (Compound 35) and 142.3 mg (0.516 mmol) of ethyl 4-iodobenzoate (compound 29) in 2 ml of triethylamine was placed in a heavy walled glass tube and degassed under argon. The mixture was then treated with a finely ground mixture of 42 mg (0.221 mmol) of cuprous iodide and 63 mg (0.09 mmol) of bis (triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed under argon again and the tube was sealed. The mixture was stirred at room temperatures for 40 hours. The triethylamine was removed under vacuum and the residue purified by flash chromatography (silica, 3% ethyl acetate in hexanes) to give the title compound as a pale yellow solid. PMR (CDCl3) : & 1.37-1.42 (15H, m), 1.96 (2H, s), 4.38 (2H, q, J~7.0 Hz), 7.25 (1H, dd, J~8.2 Hz, 1.8 Hz), 7.33 (1H, d, J~1.8 Hz), 7.37 (1H, d, J~8.2 Hz), 7.65 (2H, d, J~8.6 Hz), 8.01 (2H, d, J~8.6 Hz). MS exact mass, m/e 378.1636 (calcd. for C24H26O2S, 378.165.3).
Reaction SMILES: [N:1](OCCCC)=[O:2].[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18](C)[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+].O>CN(C)C=O.C(O)(=O)C>[C:8]1([N:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15](=[O:28])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([NH:1][OH:2])[C:17]=2[CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1C
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)N(c2ccccc2)c2ccccc2)ccc(S(C)(=O)=O)c1NO
Temperature: 0 °C

Procedure:
A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97%) and 2 g (5.3 mmol) of N,N-diphenyl-2,3-dimethyl-4-methylsulfonyl-benzamide in 30 ml of dimethylformamide is cooled to from −55 to −60° C., and a solution of 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is monitored by HPLC. For work-up, initially 10 ml of water are added, and the mixture is then adjusted to pH 5-6 using glacial acetic acid. The mixture is then poured onto 100 ml of ice-water and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.0 g of a partially crystalline crude product, which is purified by silica gel chromatography using the mobile phase toluene/acetone.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.[CH:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18].C(O)(=O)C>C1COCC1.CCCCCC>[C:8]([CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])[CH:17]([OH:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])([OH:10])=[O:9]
Reactant: COC(=O)CCCCCCC=O
Reactant: Cc1ccccc1CC(=O)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC(O)C(C(=O)O)c1ccccc1C
Reaction time: 1.5 h

Procedure:
o-Tolylacetic acid (4.56 g.) in THF (50 ml.) was treated at 5°-10° C. under argon with a 1.6M solution (36.0 ml.) of butyllithium in hexane. After 1 hour the solution obtained was added dropwise to a solution of methyl 7-formylheptanoate (5.68 g.) in dry THF (50 ml.) at -30 ° to -50° C. during 30 minutes. The mixture was stirred for 1.5 hours at the same temperature. Acetic acid (3.5 ml. ) was then added carefully and the mixture was evaporated. The residue was partitioned between ether (100 ml.) and saturated sodium bicarbonate solution (50 ml.). The aqueous layer was acidified to pH 4 (HCl) and extracted thoroughly with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated. The residual oil was purified by medium pressure liquid chromatography on silica (190 g.), eluting with 30% v/v ethyl acetate/hexane, to give methyl 9-carboxy-8-hydroxy-9-o-tolylnonanoate (A) as an oil (1.94 g., single diastereoisomer);NMR : 1-1.7 (10H,m), 2.1-2.5 (5H,m), 3.6 (3H,s), 3.8-4.3 (2H,m), 6.7 (2H,br s), 7.2 (4H,s); m/e (chemical ionisation): 323 (M+ +H), 340 (M+ +NH4).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[Al](C)C.C[O:17][C:18]([C:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29][C:30]3[CH:35]=[C:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:33]=[CH:32][N:31]=3)=[CH:28][C:23]=2[O:22][CH:21]=1)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:18]([C:20]2[C:24]3[CH:25]=[CH:26][C:27]([O:29][C:30]4[CH:35]=[C:34]([CH2:36][O:37][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:33]=[CH:32][N:31]=4)=[CH:28][C:23]=3[O:22][CH:21]=2)=[O:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1coc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc12
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1coc2cc(Oc3cc(COCc4ccccc4)ncn3)ccc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a dried vessel, 55 μl (0.44 mMol) 3-trifluoromethyl-aniline are dissolved in 6 ml toluene and cooled in an ice bath. Then 0.66 ml Me3Al (2 M in toluene; 1.32 mMol) are added via syringe. After 1 h at rt, a solution of 156 mg (0.40 mMol) 6-(6-benzyloxymethyl-pyrimidin-4-yloxy)-benzofuran-3-carboxylic acid methyl ester in 2 ml THF is added and the yellowish solution is stirred for 1¼ h in an oil bath of 110° C. The solution is cooled in an icebath and hydrolyzed with 15 ml of a sat. NH4Cl solution. After 15 min stirring, the mixture is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 4:1→EtOAc) gives the title compound: MS: [M+1]+=520; TLC(hexane/EtOAc 2:1): Rf=0.17.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>CC#N.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.1 %

Procedure:
To a solution of Compound 2 (1.86 g, 12.3 mmol) and potassium carbonate (1.70 g, 12.3 mmol) in CH3CN anhydrous (50 mL) at 0° C. was dropwise added t-Butyl-bromoacetate (2.41 g, 12.4 mmol) over 45 minute. The reaction mixture was gradually warmed to room temperature and stirred for 66 h. The resulting reaction mixture was filtered, and the filtrate was concentrated to give a white oily compound. The residue was then dissolved in CH2Cl2 (50 mL), and the resulting solution was filtered, and the filtrate was concentrated to afford white Compound 4 (2.94 g, 90%), 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.86 (t, 2H), 3.23 (s, 2H), 3.54 to 3.62 (m, 2H), 3.82 (s, 2H), 7.23 to 7.34 (m, 5H); 13C NMR (CDCl3) δ 28.00, 55.27, 26.52, 58.47, 58.84, 81.29, 127.28, 128.36, 128.81, 138.27, 171.02. HRMS (Positive ion FAB) Calcd for C15H24NO3 [M+H]+ m/z 266.3605. Found: [M+H]+ m/z 266.1756.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(O)C>[C:9]1([C:8]2[S:4][CH2:3][CH:2]([C:5]([OH:7])=[O:6])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@@H](CS)C(=O)O
Reactant: N#Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(O)C1CSC(c2ccccc2)=N1
Yield: 66 %

Procedure:
Cysteine, benzonitrile, and 5 equivalents of triethylamine were refluxed in ethanol for 6-8 hours to obtain a 66-70% yield of 2-phenylthiazoline-4-carboxylic acid. The 2-phenylthiazoline-4 carboxylic acid was reacted with 2.05 equivalents of base and 1 equivalent of methyl iodide in tetrahydrofuran at 0° C. to form 2-phenyl-4-methylthiazoline-4 carboxylic acid. The 2-phenyl-4-methylthiazoline-4 carboxylic acid can be resolved and isolated as the (S)-enantiomer using emulsion crystallization, and subsequently hydrolyzed with hydrochloric acid, thereby obtaining (S)-2-methylcysteine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[F:11].C(O)C.O.O.[Sn](Cl)Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:11]
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene was dissolved in tetrahydrofuran (75 mL) and ethanol (75 mL) and tin(II) chloride dihydrate added and the mixture left to stir at ambient temperature for 4 h. The solvent was evaporated and the residue was treated with ice-cold 2 N sodium hydroxide solution (200 mL). The resulting slurry was stirred for 30 min then extracted with dichloromethane (3×200 mL). The combined organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to give 3-bromo-4-fluorophenylamine (7.92 g, 92%) as a yellow oil: δH (360 MHz, CDCl3) 3.53 (2H, s), 6.53-6.57 (1H, m), 6.83-6.85 (1H, m), 6.90 (1H, dd, J 9 and 9).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].[F:26][C:27]([F:31])([F:30])CS>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][CH2:13][C:27]([F:31])([F:30])[F:26])=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Reactant: FC(F)(F)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(SCC(F)(F)F)sc(C(=O)N3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (15 mL) was added NaOH (0.7 mL of a 3 M solution, 2.3 mmol) followed by 2,2,2-trifluoroethanethiol (0.2 mL, 2.2 mmol). The mixture was stirred at room temperature for 3 h then evaporated. The residue was partitioned between EtOAc (20 mL) and NaOH (1M; 30 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was triturated with ether and the colourless solid (166 mg, 35%) collected by filtration. C17H20F3NO2S2 requires: C, 52.16; H, 5.15; N, 3.58%. Found: C, 51.86; H, 4.99; N, 3.61%. 1H NMR (360 MHz, CDCl3) δ 1.05 (6H, s), 1.95-1.99 (4H, m), 2.42 (2H, s), 2.86 (2H, s), 3.57-3.63 (4H, m), 3.66 (2H, q, J=9.5 Hz). MS (ES+) 392 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:27][C:28]([OH:30])=O)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][C:28]([NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reactant: NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
The mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetic acid (70 mg, 0.159 mmol), cyclohexylamine (19 mg, 0.191 mmol) EDC.HCl (36 mg, 0.191 mmol), HOBt (26 mmg, 0.191 mmol) and DIPEA (25 mg, 0.191 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and the residue was purified with chromatography to give 45 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide as a yellow solid. MS m/z 522 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].[Na+].[I-].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:1]([CH2:4][CH2:5][CH2:6][O:7][CH2:13][C:14]([OH:16])=[O:15])=[N+:2]=[N-:3]
Reactant: O=C([O-])CCl
Reactant: [N-]=[N+]=NCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCOCC(=O)O
Yield: 57.4 %

Procedure:
A solution of 3-azidopropanol (70.1 g, 0.693 mol) in 100 mL of THF was added dropwise, in a period of 1.5 hours, to a mechanically stirred suspension of NaH (60% in mineral oil, 30.5 g, 0.763 mol) in 250 mL of THF. During the addition of 3-azidopropanol, a gentle reflux was maintained. This was followed by addition of solid NaI (10.4 g, 69.3 mmol), and tetrabutylammonium bromide (22.3 g, 69.3 mmol), and sodium chloroacetate (88.8 g, 0.763 mol). The reaction mixture was heated at reflux temperature for 19 hours, cooled, quenched initially with 20 mL of water (added dropwise) and then with 700 mL of water, washed with EtOAc (3×200 mL), acidified with concentrated HCl to pH=2, and extracted with dichloromethane (6×100 mL). The combined dichloromethane extracts were dried (MgSO4), and the solvent was removed in vacuo to give 63.3 g (58%) of the title compound as a yellow viscous oil. The crude product was used in the next step after spectral characterization.
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]#[N:5].[CH3:14][C:15]([CH3:20])=[CH:16]B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:9]1[C:2]([CH:14]=[C:15]([CH3:20])[CH3:16])=[C:3]([C:6]([N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c([N+](=O)[O-])ccc(F)c1Br
Reactant: CC(C)=CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)=Cc1c(F)ccc([N+](=O)[O-])c1C#N
Temperature: 70 °C
Yield: 79 %

Procedure:
2-Bromo-3-fluoro-6-nitrobenzonitrile (Example 134d) (0.62 g, 2.53 mmol), 2-methylprop-1-enylboronic acid (0.50 g, 5.05 mmol), palladium(II) acetate (0.023 g, 0.102 mmol), K3PO4 (1.61 g, 7.58 mmol), and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.083 g, 0.202 mmol) were suspended in anhydrous THF (16 mL) under nitrogen and heated at 70° C. for 4.5 h. Solvent was removed under vacuum, and the product was purified by chromatography on silica gel eluting with gradient 0% to 100% ethyl acetate in hexanes, to give 3-fluoro-2-(2-methylprop-1-enyl)-6-nitrobenzonitrile 0.44 g (78%) as a yellow solid. MS 221 (MH+).