Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[NH:5][C:6](=[O:32])[C@@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[N:8]([C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)[CH3:9].O.[OH-].[Li+].O>CO.O1CCCC1>[CH3:18][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([CH3:17])[CH:14]=1)[C:10]([N:8]([CH3:9])[C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:32])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[O:31][N:30]=[CH:29][CH:28]=2)=[CH:25][CH:26]=1)=[O:19]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)N(C)[C@H](Cc2ccc(-c3ccno3)cc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1
Reaction time: 2 h

Procedure:
[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane methyl ester (50 mg) is treated with lithiumhydroxide monohydrate (3.8 mg) in methanol (1 ml), tetrahydrofurane (0.5 ml), and water (0.5 ml), at 0° C. for 1 hour, and at room temperature for 2 hours. The mixture is then partitioned between water and ether, the water phase acidified with 1N hydrochloric acid, and subsequently extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, and evaporated to give [N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-tryptophane.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])C=C)([OH:3])=[O:2].[Cl-].C[N+]1C=CN(CC)C=1.[Cl-].[Cl-].[Cl-].[Al+3]>[Ru].CCCCCC.C(C1C=CC=C(C(C)C)C=1N=CC1C=C([N+]([O-])=O)C=CC=1[O-])(C)C.C(=[Ru+]Cl)C1C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[C:1]([CH2:4][NH:5][C:6]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=1)([OH:3])=[O:2]
Reactant: C=CCCCC(C=C)NCC(=O)O
Agent: Cl[Ru+]=Cc1ccccc1
Agent: [Ru]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCCCCC
Product: O=C(O)CNC1=CCCCC1

Procedure:
92 mg (0.5 mmol) of N-carboxymethyl-3-amino-1,7-octadiene and 10 mg of the ruthenium catalyst shown in the reaction scheme above, namely (tricyclohexylphosphine)-benzylidene-chloro-ruthenium-(IV) 2-[(2,6-diisopropylphenyl)imino]methyl-4-nitro-phenoxide, were dissolved in 1 ml of absolute hexane and a mixture of 290 mg (2 mmol) of 1-methyl-3-ethylimidazolium chloride and 266 mg (2 mmol) of aluminium trichloride under an argon atmosphere in a baked-out Schlenk tube. The mixture was allowed to react for 3 hours at 50° C. For the work-up, the organic phase was pipetted off and the phase comprising the ionic liquid was washed twice with 2 ml each time of hexane. The combined hexane phases were evaporated. Finally, the mixture was filtered through a very short silica gel column (0.2 cm), washed once with 1 ml of acetonitrile and evaporated. The catalyst dissolved in the ionic liquid is available for a further reaction with substrate in hexane.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[F:5][C:6]1[C:11]([N:12]=[N:13][N:14]2CCCC2)=[C:10]([F:19])[CH:9]=[CH:8][C:7]=1[CH:20]1[CH2:24][NH:23][C:22](=[O:25])[CH2:21]1>Cl>[N:12]([C:11]1[C:6]([F:5])=[C:7]([CH:20]2[CH2:24][NH:23][C:22](=[O:25])[CH2:21]2)[CH:8]=[CH:9][C:10]=1[F:19])=[N+:13]=[N-:14]
Reactant: O=C1CC(c2ccc(F)c(N=NN3CCCC3)c2F)CN1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1c(F)ccc(C2CNC(=O)C2)c1F
Reaction time: 1.5 h

Procedure:
In a 25 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, NaN3 (0.133 g, 2 mmol) is added to a solution of 4-[2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-pyrrolidin-2-one a13 (0.2 g, 0.68 mmol) and HCl (1 N, 10 ml) at room temperature. After 1.5 h, the reaction mixture is quenched by NaOH (1N, 10 ml), extracted with CH2Cl2 (3 times), and the organic layer is dried on MgSO4, filtered and concentrated in vacuo to afford the crude 4-(3-azido-2,4-difluoro-phenyl)-pyrrolidin-2-one a14 which is used as such in the next step.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:20][C@@H:21]1[CH2:24][C@H:23]([CH2:25][OH:26])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([NH:20][C@@H:21]1[CH2:24][C@H:23]([CH2:25][O:26][N:28]2[C:32](=[O:33])[C:31]3[C:30](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]2=[O:38])[CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CON2C(=O)c3ccccc3C2=O)C1

Procedure:
A solution of 6.54 ml (0.0391 mol) of diethyl azodicarboxylate (93%) in 30 ml of benzene is added dropwise to a mixture of 7.5 g (0.03726 mol) of cis-3-(N-BOC-amino)-cyclobutanemethanol, 6.08 g (0.03726 mol) of N-hydroxyphthalimide, 9.774 g (0.03726 mol) of triphenylphosphine and 120 ml of benzene at 20°-30° C., while stirring. The reaction mixture is stirred at room temperature for 2 hours and filtered, the crystalline residue (diethyl 1,2-hydrazinedicarboxylate) is washed with benzene and the filtrate is evaporated in vacuo. The residue is purified by means of flash chromatography on silica gel using ethyl acetate/hexane mixtures (1:3 and 1:2). After evaporation of the product-containing fractions and recrystallization of the residue from ethyl acetate/hexane, the title compound is obtained, m.p. 131.5°-132.5° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.ClCCl.[C:26]1([S:32]([N:35]2[C:39]3=[N:40][CH:41]=[C:42]([CH:44]4[CH2:48][O:47][C:46]([CH3:50])([CH3:49])[O:45]4)[CH:43]=[C:38]3[CH:37]=[C:36]2[CH:51]([OH:58])[CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([S:32]([N:35]2[C:39]3=[N:40][CH:41]=[C:42]([CH:44]4[CH2:48][O:47][C:46]([CH3:49])([CH3:50])[O:45]4)[CH:43]=[C:38]3[CH:37]=[C:36]2[C:51](=[O:58])[CH2:52][CH:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC1(C)OCC(c2cnc3c(c2)cc(C(O)CC2CCCC2)n3S(=O)(=O)c2ccccc2)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)OCC(c2cnc3c(c2)cc(C(=O)CC2CCCC2)n3S(=O)(=O)c2ccccc2)O1
Reaction time: 1 h
Yield: 106.2 %

Procedure:
A Dess-Martin periodinane solution in dichloromethane (0.3 M, 35 mL, 10.5 mmol) was added to 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanol (1.7 g, 4.62 mmol) at 25° C. and then stirred for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate (3×30 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-[1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-cyclopentyl-ethanone (2.3 g crude) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C25H28N2O5S [M+H]+ 469.58, observed 469.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (m, 2H), 1.57-1.73 (m, 4H), 1.52 (s, 3H), 1.59 (s, 3H), 1.96 (m, 2H), 2.44 (m, 1 H), 3.03 (d, J=7.2 Hz, 2H), 3.74 (dd, J=7.6 Hz, 8.4 Hz, 1H), 4.39 (dd, J=6.4 Hz, 8.4 Hz, 1H), 5.19 (dd, J=6.4 Hz, 7.6 Hz, 1H), 6.94 (s, 1H), 7.55 (m, 2H), 7.62 (m, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.39 (d, J=7.6 Hz, 2H), 8.56 (d, J=2.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)ccc1O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Yield: 95.6 %

Procedure:
To a mixture of 5-fluoro-2-hydroxybenzoic acid (3.08 g, 19.76 mmol) in concentrated H2SO4 (30 mL) below 0° C. was added dropwise a mixture of concentrated HNO3 (2.11 g, 21.74 mmol) and concentrated H2SO4 (6 mL) with stirring below 5° C. After the addition, the mixture was stirred at this temperature for 2 hr. The reaction mixture was poured onto crash ice and the precipitate was collected, then the precipitate was dissolved in ethyl acetate (100 mL), washed with water (50 mL×2), brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give 5-fluoro-2-hydroxy-3-nitrobenzoic acid (3.8 g) as a brown solid. LC-MS (ESI) m/z 202 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: C=CCCCBr
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 62%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.17 mmol). 1H NMR (CDCl3, 300 MHz) δ 1.62-1.75 (br, 2H), 2.01-2.22 (m, 7H), 2.35-2.53 (br, 3H), 2.58-2.65 (m, 1H), 2.74 (t, J=6.6 Hz, 2H), 2.75-2.85 (br, 1H), 2.88-3.05 (br, 1H), 3.28-3.41 (m, 3H), 4.97 (d, J=13.5 Hz, 1H), 5.02 (dd, J=17.6, 1.5 Hz, 1H), 5.73-5.83 (m, 1H), 6.93 (s, 1H), 6.98 (s, 1H), 7.15-7.21 (m, 2H), 7.36-7.40 (m, 1H) ppm. MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:3]([C:5]2[N:6]=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Br:20])[NH:8][C:9](=[O:12])[C:10]=2[OH:11])=[O:4])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Product: O=C(NCc1ccc(Cl)cc1)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and 4-chlorobenzylamine (0.5 ml; 4.1 mmol). The title compound was prepared as a white solid (0.042 g; 39%). LCMS: m/z=449 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH:30]C(OCC3C=CC=CC=3)=O)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH2:30])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(NC(=O)OCc3ccccc3)CCOCC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CCOCC2)cc1
Reaction time: 1 h

Procedure:
The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium-on-charcoal are added and the mixture is hydrogenated at atmospheric pressure. After 1 hour, the catalyst is filtered off and the filtrate is then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/methanol/33% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 0.93 g of the expected product in the form of a white solid. M.p.=125°-127° C.
Reaction SMILES: [N+](C1C=CC=CC=1OC1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2)([O-])=O.[OH:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][CH2:31]2.[OH-].[K+].Cl[C:47]1[C:52]([N+:53]([O-:55])=[O:54])=[CH:51][C:50]([C:56]([F:59])([F:58])[F:57])=[CH:49][C:48]=1[N+:60]([O-:62])=[O:61]>CS(C)=O>[N+:53]([C:52]1[CH:51]=[C:50]([C:56]([F:57])([F:58])[F:59])[CH:49]=[C:48]([N+:60]([O-:62])=[O:61])[C:47]=1[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[O:34][CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][CH2:31]2)([O-:55])=[O:54]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Oc1ccc2c(c1)CCC(c1ccccc1)O2

Procedure:
2,6-Dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene was prepared as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavane (0.453 g) was used in 10 ml of dry DMSO under nitrogen. Also KI (0.498 g) and KOH (0.224 g) and 4-chloro-3,5-dinitro benzotrifluoride (0.541 mg) were added in similar manner. 1H-NMR (400 MHz; d6-DMSO): δ 8.87 (s, 2H), 7.46-7.29 (m, 5H), 6.89-6.75 (m, 4H), 5.09 (dd, 1H, J=10.3 Hz, J=2.1 Hz), 2.98-2.85 (m, 1H), 2.75-2.62 (m, 1H), 2.19-2.08 (m, 1H), 2.03-1.88 (m, 1H).
Reaction SMILES: N[C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Br
Reactant: COC(=O)c1cccc(N)c1Cl
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (2.0 g, 11 mmol) in 48% HBr (10 mL) and water (20 mL) was added an aqueous solution of sodium nitrite (0.89 g, 13 mmol) at 0° C. The mixture was allowed to stir at 0° C. for 30 minutes before it was added into a suspension of copper(I) bromide (2.3 g, 16 mmol) in water (10 mL) and 48% HBr (5 mL) at 0° C. The reaction was allowed to warm to RT slowly, and then heated to 60° C. for 5 minutes. TLC and LC suggested good reaction. The product was extracted with DCM (100 mL×2). The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC to deliver methyl 3-bromo-2-chlorobenzoate. LC-MS (IE, m/z): 251 [M+1]+;
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[NH2:16][C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:16][C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 102.4 %

Procedure:
4-Aminomethyl-1-tert-butoxycarbonylpiperidine (10.0 g) was dissolved in dimethylformamide and 4-amino-5-chloro-2-methoxybenzoic acid (9.4 g) and 1-hydroxybenzotriazole (6.6 g) were added. After stirring at 0° C. for 40 min, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (9.4 g) was added, and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 19.0 g of 4-amino-5-chloro-N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH:8]=[C:9](SC)SC>C(O)C>[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH:8]=[C:9]1[NH:1][CH2:2][CH2:3][S:4]1
Reactant: NCCS
Reactant: CSC(=CC(=O)C(F)(F)F)SC
Solvent: CCO
Product: O=C(C=C1NCCS1)C(F)(F)F
Temperature: 25 °C
Reaction time: 13 h
Yield: 80.5 %

Procedure:
A solution of 36 mg (0.46 mmol) of 2-aminoethanethiol dissolved in 10 mL of ethanol was added to 100 mg (0.46 mmol) of 1,1,1-trifluoro-4,4-bis(methylthio)-3-buten-2-one obtained by the method described in Comparative Example 4, and the mixture was refluxed under heating for 6 hours, then stirred at room temperature for 13 hours. Following reaction completion, the ethanol was distilled off under reduced pressure, after which the condensate was dissolved in ethyl acetate and washed once with water. The washed product was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure, giving 73 mg (yield, 81%) of 1,1,1-trifluoro-3-(thiazolidin-2-ylidene)propan-2-one.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: Nc1cccc(Br)c1
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: COCCOC
Product: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
2,3-dihydrobenzofuran-5-boronic acid (0.114 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.0762 g in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH2:35]=O>>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:28])[N:19]([C@H:23]5[CH2:27][CH2:26][N:25]([CH3:35])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC1
Reactant: C=O
Product: CN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-1-methylpyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S)-pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 114) and formaldehyde following General Procedure R.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=[O:22])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:29][CH2:30]3)=[O:22])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 944.7 %

Procedure:
To 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 200 mg, 0.52 mmol), tert-butyl 4-piperidinylcarbamate (1 eq, 105 mg, 0.052 mmol), and triethylamine (3 eq, 0.22 mL, 1.57 mmol) was added (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 eq, 232 mg, 0.52 mmol). The reaction was stirred 16 h and then concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 277 mg (93%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 11H) 1.95-2.10 (m, 2H) 2.14-2.25 (m, 3H) 2.97 (br. s., 1H) 3.25 (d, J=7.63 Hz, 1H) 3.66-3.82 (m, 1H) 4.31 (d, J=13.37 Hz, 1H) 4.49 (d, J=5.84 Hz, 1H) 4.66 (d, J=13.09 Hz, 1H) 7.03-7.10 (m, 2H) 7.12-7.18 (m, 1H) 7.21-7.34 (m, 3H) 7.45 (d, J=2.07 Hz, 1H); [M+Na]+ 587.4.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2)=[O:16].[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:32]=CC=C[CH:28]=1.C(O)(C)C>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([O:26][CH:27]([CH3:32])[CH3:28])[CH:22]=[CH:21][CH:20]=2)=[O:16]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(OC(C)C)cccc2[nH]1
Reaction time: 0.33 h

Procedure:
DEAD (0.227 ml, 1.47 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (200 mg, 1.05 mmol), triphenylphosphine (384 mg, 1.47 mmol) and isopropanol (0.108 ml, 1.43 mmol) in 2 ml of THF. Stirring is continued for 20 minutes and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using cyclohexane/EtOAc (9/1).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]([N:16]=[C:17]=[O:18])[CH3:15]>>[CH2:1]([NH:13][C:17]([NH:16][CH2:14][CH3:15])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN
Reactant: CCN=C=O
Product: CCCCCCCCCCCCNC(=O)NCC
Temperature: 50 °C

Procedure:
Dodecylamine (370 g) was placed in 80/100° fraction petroleum ether (1.5 litre) and stirred in a flask fitted with a dipping thermometer, tap funnel and reflux condenser. A mixture of ethyl isocyanate (142 g) and petroleum ether (150 ml) was run in slowly whilst external cooling was applied to the flask. The temperature was allowed to reach but not exceed 50° C. The mixture was stirred for 1 hour after the addition was complete, maintaining the temperature at about 50° C. The reaction was then allowed to cool and the copious white precipitate (which had begun to separate as soon as the isocyanate addition commenced) was filtered off, pressed well and washed with about 300 ml petroleum ether. The white mass was dried in vacuum at 50° C. to give a quantitative yield (512 g) with a melting point of 84° to 87° C. The product was not subjected to any further purification before use.