Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH:24]=O)[CH:20]=[CH:19][C:18]=3[N+:26]([O-:28])=[O:27])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(OCC)C.ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH2:23][CH2:24][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:20]=[CH:19][C:18]=3[N+:26]([O-:28])=[O:27])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2cc(CC=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1CCN(CCc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.200 g (0.43 mmole) of 4-(3-chloro-phenyl)-2-[5(2,2-dimethoxy-ethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.9a) and 3 mL of 96% formic acid was stirred at room temperature for 1 hour. The solution was poured into water and the resulting precipitate was collected by filtration, washed with water and air-dried to give 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b) as an orange solid. A mixture of 0.135 g of 4-(3-chloro-phenyl)-2-[2-nitro-5-(2-oxo-ethyl)-phenylamino]-thiazole-5-carboxylic acid amide (VI.9b), 0.10 mL of N-methylpiperazine, 0.10 mL of glacial acetic acid, 0.50 g of sodium triacetoxyborohydride and 10 mL of dichloromethane was stirred at room temperature for 16 hours. To the mixture was carefully added 1 mL of 1M hydrochloric acid and stirring was continued at room temperature for 30 minutes. The mixture was partitioned between 30 mL of dichloromethane and 30 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed once with 30 mL of water, then 30 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 15:85-20:80) to give an orange foam. Trituration with diethyl ether gave 0.100 g of 4-(3-chlorophenyl)-2-{5-[2-(4-methyl-piperazin-1-yl)-ethyl]-2-nitro-phenylamino}-thiazole-5-carboxylic acid amide (VI.9c) as an orange solid.
Reaction SMILES: [C:1]([NH:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:21][N:22]=[C:23]=[O:24]>C(Cl)(Cl)Cl>[C:1]([NH:4][N:5]([C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])[C:23](=[O:24])[NH:22][CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)N(NC(C)=O)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 40 °C

Procedure:
Trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, 330 dissolved in 4 ml of chloroform, 0.3 ml of methyl isocyanate was added to this, and the mixture was heated on a water bath at 40° C. for 130 minutes. The solvent was distilled off under a reduced pressure and the residue obtained was recrystallized from ethyl acetate-ethanol to give 350 mg of trans-4-(2-acetyl-1-methylcarbamoylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol.monohydrate as white crystals, m.p. 225°-226° C. (decomposed).
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.[F:29][CH:30]([F:62])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([OH:53])=O)=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:45]2=[N:46][CH:47]=1>CN(C=O)C>[F:62][CH:30]([F:29])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([NH:16][CH:11]([CH3:12])[CH3:10])=[O:53])=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:59])([CH3:60])[CH3:61])[C:45]2=[N:46][CH:47]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) and DMF (2 mL). The reaction mixture was stirred at 25° C. for 15 h. Propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) and HATU (28.0 mg, 73.5 μmol) were added. After 3 h the solvents were evaporated and the residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 50% EtOAc in hexanes over 30 min) to yield 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32.5 mg, 61.3 μmol, 100%) as a light yellow solid. MS (M+Na)+=553.1; 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.45-7.53 (m, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.53 (t, J=74.0 Hz, 1H), 5.73 (s, 2H), 4.38-4.59 (m, 1H), 4.21 (s, 3H), 3.55-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.88-1.03 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:25])[CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].[BH4-].[Na+]>C(O)(C)C.O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:26])([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:25])[CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:23])[CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCC(C)(C)CCCC(=O)CCCCCC(C)(C)C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)CCC(C)(C)CCCC(O)CCCCCC(C)(C)C(=O)OCC
Temperature: 45 °C
Yield: 97.7 %

Procedure:
To a solution of 2,2,12,12-tetramethyl-8-oxopentadecanedioic acid diethyl ester (33.6 g, 84.3 mmol) in 60% aqueous isopropanol (337 mL) was added sodium borohydride (1.6 g, 41 mmol). The reaction mixture was heated to 45° C. for 2 h, diluted with water (400 mL), and extracted with MTBE (2×200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product (33.0 g, 98%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, J=7.2 Hz, 4H), 3.55-3.45 (m, 1H), 1.60-1.18 (m, 26H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 178.1, 72.0, 60.3, 42.4, 40.9, 37.7, 30.4, 25.8, 25.4, 25.1, 14.5. HPLC: 87.5% pure.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[S:11][C:12]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:13]=2[N:14]=1.[OH-].[Na+]>O.O1CCOCC1>[F:21][C:15]1[C:13]2[N:14]=[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])[S:11][C:12]=2[C:18]([F:19])=[CH:17][C:16]=1[F:20]
Reactant: COC(=O)CCCCCCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.6 %

Procedure:
To a solution of 7-(4,5,7-trifluorobenzothiazol-2-yl)heptanoic acid methyl ester (407 mg, 1.2 mmol) in a mixture of water (7 ml) and dioxane (7 ml) was added dropwise aqueous 2N sodium hydroxide (4 ml) at room temperature and the mixture was stirred for 5 hours at room temperature. To the mixture further aqueous 2N sodium hydroxide (2 ml) was added dropwise and the resulting mixture was stirred for 1 hour, then diluted with water and extracted with ethyl acetate. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a residue, which was crystallized from isopropyl ether to give 7-(4,5,7-trifluorobenzothiazol-2-yl)heptanoic acid (189 mg, 50%) as a colorless powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39].O.[NH2:42][NH2:43]>CS(C)=O>[NH:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:37])[CH:10]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39])[NH2:43]
Reactant: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(NN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(4-Fluoro-3-nitrophenyl)-2-[4-(4-hydroxyphenylsulphonyl)-phenoxy]undecylamide (86.0 g, 147.0 mmole) was dissolved in dimethyl sulphoxide (500 ml), and hydrazine monohydrate (17.8 g, 355 mmole) was added in a dropwise fashion whilst keeping the temperature below 40° C. The reaction mixture was stirred for 1.5 hr at room temperature, and was then drowned in an ice/brine mixture (61). The red solid obtained was filtered off and dried at room temperature. The product was used in this crude form without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@H:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)=[O:22]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=2)=[CH:30][CH:31]=1)[OH:33])=[O:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 110 °C
Yield: 53.8 %

Procedure:
To solution of commercially available (4-(((tert-butoxycarbonyl)-amino)methyl)-phenyl)boronic acid (1.01 gm, 4.02 mmol) in 1,4-dioxane:water (12.3:3.8 mL) is added 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)acetamide (1.04 g, 2.56 mmol) and CS2CO3 (1.85 g, 5.67 mmol) and the resulting solution bubbled with nitrogen gas for 30 min. To this reaction mixture is added Pd(PPh3)4 (0.332 g, 0.29 mmol) and the resulting reaction mixture heated to 110° C. for 2 hours. The resulting reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer dried over sodium sulfate and concentrated to give a crude residue, which is purified using column chromatography on silica gel eluting with 30% Ethyl acetate/hexane to give the title compound (668 mg). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 8H), 4.30-4.32 (m, 1H), 4.34-4.35 (m, 2H), 4.44-4.47 (m, 0.5H), 4.55-4.59 (m, 1H), 4.68-4.69 (m, 0.5H), 4.85 (m, 1H), 5.15 (t, 1H, J=7.04 Hz), 5.87 (s, 1H), 7.04 (d, 1H, J=8.6 Hz), 7.34 (d, 2H, J=7.92 Hz), 7.44 (d, 2H, J=8.2 Hz), 7.53 (d, 2H, J=8.08 Hz), 7.57 (d, 2H, J=8.08 Hz). m/z (Cl) M−H 483
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:24]([C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[F:32])#[N:25].[Cl-].[NH4+]>O1CCCC1>[C:24]([C:26]1[CH:27]=[C:28]([S:33]([N:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[F:32])#[N:25]
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a stirred solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 72, 0.500 g, 0.002497 mol) in tetrahydrofuran (10.0 mL) was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M solution in tetrahydrofuran, 2.50 mL, 0.0025 mol) at 0° C. under nitrogen. After stirring for 1 hour at 0° C. the reaction mixture was cooled to −78° C. and 3-cyano-4-fluorobenzenesulfonyl chloride (0.453 g, 0.002063 mol) in tetrahydrofuran (5.0 mL) was added. The mixture was warmed to room temperature for 16 hours. Saturated aqueous ammonium chloride solution (20.0 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20.0 mL). Combined organic layers were dried over sodium sulfate and concentrated in vacuo. This crude residue was purified using ISCO™ (12 g SiO2) eluting with ethyl acetate:dichloromethane (gradient 0:1 to 3:7, by volume) to afford the title compound as a white solid, 426 mg, 54% yield.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.[C:28]([N:32]1[C:36](=[O:37])[CH:35]=[C:34](Cl)[S:33]1(=[O:40])=[O:39])([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].ClCCl>O1CCOCC1.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]>[C:28]([N:32]1[C:36](=[O:37])[CH:35]=[C:34]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C@H:3]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:2][OH:1])=[CH:10][CH:9]=2)[S:33]1(=[O:39])=[O:40])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)N1C(=O)C=C(Cl)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1
Temperature: 90 °C
Yield: 163.5 %

Procedure:
Combined 34-A (6.1 g, 61 mmol), 9-A (3.55 g, 15.9 mmol), potassium carbonate (10.0 g, 72.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (2.50 g, 3.06 mmol) in 200 mL dioxane. The reaction was degassed and heated at 90° C. for 48 hours. The crude was extracted with ethyl acetate, washed with water and brine. The combined organic extracts were dried over Na2SO4, filtered and evaporated to give 11.4 g of a dark glass. The crude was chromatographed on a silica column to afford a dark semi-solid (3.3 g, 90%). 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 6.62 (s, 1H), 4.77 (br s, 1H), 3.89 (br s, 1H), 3.69 (m, 1H), 3.58 (m, 1H), 2.93 (d, J=7.2 Hz, 2H) 1.43 (s, 9H), 1.39 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.COC(=O)[O-].C([N+](CC)(CC)C)C.[CH:24]#[N:25].OP(O)(O)=O>>[O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:24]([C:4]1([CH3:10])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1)#[N:25]
Reactant: C#N
Agent: CC[N+](C)(CC)CC
Agent: COC(=O)[O-]
Agent: O=P(O)(O)O
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CC(=O)CC(C)(C#N)C1
Reaction time: 2 h

Procedure:
To 622 g (4.5 mol) of isophorone in the presence of 4 g (0.021 mol) of triethylmethylammonium methylcarbonate there are added 288.3 g of a mixture of 3 mol of HCN and 1.5 mol of isophorone, over a period of 120 min and at a reaction temperature of 120° C. The HCN conversion at the end of the reaction is 99.9%. Following neutralization with 2.4g of H3PO4 the mixture is distilled. There are obtained 424.1 g of isophorone and 479.2 g of 3-cyano-3,5,5-trimethylcyclohexanone: the distillation residues weigh 12.8 g, this is equivalent to 1.4% based on the crude product used. The 3-cyano-3,5,5-trimethylcyclohexanone yield is thus 96.7% and the isophorone selectivity 99%.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)#[CH:12]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:15]1[CH:14]=[C:13]([C:11]#[C:12][C:2]2[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(C)c(N)c(Br)n1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(N)c(C#Cc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of Cul (41 mg, 0.2 mmol) in triethylamine (12 ml) were added 2-bromo-4,6-dimethyl-pyridin-3-ylamine (870 mg, 4.33 mmol), (PPh3)2PdCl2 (152 mg, 0.22 mmol), and 1-ethynyl-3-fluorobenzene (500 μl, 4.33 mmol). The reaction mixture was stirred for 30 min. at room temperature and for 3 h under reflux. The solvent was evaporated and the crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 4:1) to yield 745 mg (3.10 mmol, 72%) of (2-(3-fluoro-phenylethynyl)-4,6-dimethyl-pyridin-3-yl)amine as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:17])=[O:16]
Reactant: Cc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: Cc1ccccc1NS(=O)(=O)c1ccccc1

Procedure:
The so far single industrially feasible synthesis is described by BIOS Final Report 986/2, No. 167, pages 297-306, and involves acylating 2-aminotoluene with benzenesulfonyl chloride to give N-(2-methylphenyl)-benzenesulfonamide, nitrating the latter in chlorobenzene, and, finally, splitting off the protective group by hydrolysis and isolating 2-amino-5-nitrotoluene. This synthesis gives a yield of about 75% of theory. In addition to this unsatisfactory yield, the numerous process stages and the associated consumption of chemicals, this process harbors further grave disadvantages which render its industrial application problematical from a processing and an ecological point of veiw
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:16]([O:15][CH:13]1[CH2:12][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:14]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (8.5 g, 37.2 mmol) (obtained as described in Reference Example 1(2)) in dimethylformamide (255 ml) were added t-butyldiphenylsilyl chloride (19.4 ml, 74.5 mmol) and imidazole (5.07 g, 74.5 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature for 2.5 hours. After checking the completion of the reaction, ethanol (2.59 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (14.85 g, yield 86%) as a pale brown solid.
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:15]O.O>C(O)(=O)C>[CH:1]1[C:14]2[S:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Solvent: CC(=O)O
Solvent: O
Product: O=S1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 83 %

Procedure:
100 g (0.5 mole) of phenoxathiin was dissolved in 1,600 g of acetic acid, after which 48.5 g (0.5 mole) of 35% hydrogen peroxide was added dropwise to the solution. The solution was further stirred for seven days at room temperature. Then, 3,000 g of water was added to the reaction solution to settle out white crystals. The crystals were collected by filtration and dried in vacuum, obtaining the target compound. White crystals, 90 g (yield 83%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2ccc(OC(C)C)c(C#N)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CCC(=O)O)ccc1-c1noc(-c2ccc(OC(C)C)c(C#N)c2)n1
Yield: 86.9 %

Procedure:
A solution of 23 mg (0.05 mmol) of tert-butyl 3-(4-(5-(3-cyano-4-isopropyloxyphenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from Step A) in 4:1 v/v CH2Cl2/TFA was stirred at rt for 30 min. The mixture was concentrated. Purification by HPLC B gave 17 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.47 (d, J=6.2, 6H), 2.66 (s, 3H), 2.74 (t, J=7.8, 2H), 3.01 (t, J=7.8, 2H), 4.76-4.82 (m, 1H), 7.11 (d, J=9.0, 1H), 7.19-7.21 (m, 2H), 8.01 (d, J=8.3, 1H), 8.33 (dd, J=2.3, 8.9, 11H), 8.42 (d, J=2.1, 1H).