Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[OH:55][CH:56]1[CH2:61][CH2:60][N:59]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:58][CH2:57]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC(O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 4-hydroxypiperidine (1 M solution in MeOH, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (93 mg, 73%) which was obtained as a white solid. MS: m/e=394.2 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24]#[N:25])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:33][OH:34]>C(O)C>[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24](=[N:33][OH:34])[NH2:25])=[O:15])=[CH:12][CH:13]=1
Reactant: NO
Reactant: CON=C1C[C@@H](C#N)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 81.8 %

Procedure:
According to the general method outlined above for the synthesis of Intermediates 8, triethylamine (1.94 ml, 13.94 mmol) was slowly added to a suspension of (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbonitrile (3.71 g, 11.62 mmol) and hydroxylamine.hydrochloride (0.97 g, 13.94 mmol) in ethanol (150 ml), under stirring. The reaction mixture was allowed to stir at 80° C. for 16 h, and then cooled to ambient temperatures. The solvent was removed by evaporation and the solid was suspended in water (100 ml) then filtered. The solid was washed with diethyl ether (2×100 ml) whilst on the sinter and then dried in vacuo at 40° C., to give the desired product, (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (3.35 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([O:21]C)=O)[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[S:26][CH:27]=[CH:28][N:29]=1.B(OCCCC)(OCCCC)OCCCC.CO>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12]([OH:23])=[C:13]([C:19]([NH:24][C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[O:21])[N:14]([CH3:18])[S:15](=[O:17])(=[O:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(O)c2c(c3cc(Cl)ccc3n2C)S(=O)(=O)N1C
Reactant: Nc1nccs1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3cc(Cl)ccc3n2C)S1(=O)=O
Yield: 70 %

Procedure:
3.0 gm (8.4 millimols) of methyl 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide, 0.9 gm (9 millimols) of 2-amino-thiazole and 50 mgm of tri-n-butyl borate were refluxed in 300 ml of dry xylene for 6 hours. The methanol released by the reaction was separated by means of a 4-A-molecular sieve in a Soxhlet-attachment. 3.1 gm of crystals were separated from the cooled reaction mixture by filtration and subsequently boiled in a mixture of 100 ml of acetonitrile and 1 ml of glacial acetic acid. After filtration and drying, 2.5 gm (68% of theory) of 8-chloro-2,5-dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide were obtained; M.p.: 282° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C-:19]#[N:20].C([Al+]CC)C.C1(C)C=CC=CC=1>C1COCC1>[C:19]([CH:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:20]
Reactant: CCOC(=O)C(=Cc1ccc(C)s1)C(=O)OCC
Reactant: [C-]#N
Agent: CC[Al+]CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C#N)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 50.60 g (0.189 moles) sample of diethyl 2-[(5-methyl-2-thienyl)methylene]propanedioate, the product of Example 1a., was taken up in 560 ml dry THF. The solution was cooled in an ice bath. 560 ml of 1N diethyl aluminum cyanide in toluene (0.57 moles) was added dropwise over one hr. The ice bath was then removed and the reaction was stirred at room temperature for 1.5 hr. After this time the reaction was cooled again in an ice bath and 168 ml of 3N sodium hydroxide was added slowly. This was stirred for one hr. The reaction was partitioned between methylene chloride and water, the organics were washed with water, brine, and dried (MgSO4). The solvents were evaporated in vacuo. The residue was distilled in a Kugelrohr at 140° C. and 0.005 mm Hg. 117.17 g of diethyl 2-[cyano(5-methyl-2-thienyl)methyl]-propanedioate was collected as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:17]3[C:31]([CH:32]=[CH2:33])=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:41]1[CH:42]=[C:43]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:44]=[CH:45][CH:46]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[C:17]3[C:31](/[CH:32]=[CH:33]/[C:45]4[CH:46]=[CH:41][CH:42]=[C:43]([N:47]5[CH2:51][CH2:50][CH2:49][C:48]5=[O:52])[CH:44]=4)=[N:30][N:29]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][O:35]4)[C:18]=3[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reactant: O=C1CCCN1c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(-c3ccc(O)cc3)nc3c2c(/C=C/c2cccc(N4CCCC4=O)c2)nn3C2CCCCO2)CC1
Temperature: 125 °C
Yield: 67 %

Procedure:
To a solution of 4-[6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (0.30 g, 0.56 mmol) in DMF (2.55 mL) were added 1-(3-iodo-phenyl)-pyrrolidin-2-one (0.19 g, 0.67 mmol), tri(o-tolyl)phosphine (34 mg, 0.11 mmol) and triethylamine (2.55 mL). The resulting solution was degassed using argon, palladium acetate (6 mg, 0.03 mmol) was then added and the reaction mixture was heated at 125° C. overnight. The reaction mixture was concentrated under vacuum and the residue taken up in water and then acidified to pH=1. The precipitate was filtered, washed with water and then dried under vacuum. The crude residue was purified by silica gel column chromatography using a gradient of EtOAc (0-100%) in cyclohexane to yield the title compound as a beige solid (0.26 g, 66%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH2:29].[OH2:30].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].O>C(#N)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26]([CH3:27])(=[O:30])=[O:29])[N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O
Reactant: CSc1nccc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)n1
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccnc(S(C)(=O)=O)n1
Yield: 89.9 %

Procedure:
A suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(1H)-one 0.28 g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate 90.6 g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0 ml) was stirred at room temperature for 16 h. The resulting clear solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to afford the title compound (0.27 g, 90%) as a pale yellow substance: 1H NMR (CD3OD/400 MHz) δ 8.91 (d, 1H, J=5.2 Hz), 7.63 (d over m, 2H, J=5.2 Hz), 7.03 (m, 2H), 6.58 (s, 1H), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H), and 2.49 (s, 3H); 19F NMR (CD3OD/400 MHz) δ −111.58 (m), −115.98 (m); ES-HRMS m/z 500.0113 (M+H C19H17N3O4BrSF2 requires 500.0086).
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[CH3:60][N:61]([CH3:88])[C:62]([N:64]1[CH2:69][CH:68]=[C:67]([C:70]2[NH:87][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[C:82]([F:84])[CH:81]=[C:80]([NH2:85])[C:79]=4[CH3:86])[C:72]=3[CH:71]=2)[CH2:66][CH2:65]1)=[O:63].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[F:103][C:104]([F:118])([F:117])[C:105]([C:108]1[CH:116]=[CH:115][C:111]([C:112](O)=[O:113])=[CH:110][CH:109]=1)([OH:107])[CH3:106]>>[CH3:88][N:61]([CH3:60])[C:62]([N:64]1[CH2:65][CH:66]=[C:67]([C:70]2[NH:87][C:73]3[N:74]=[CH:75][N:76]=[C:77]([C:78]4[CH:83]=[C:82]([F:84])[CH:81]=[C:80]([NH:85][C:112](=[O:113])[C:111]5[CH:115]=[CH:116][C:108]([C:105]([OH:107])([CH3:106])[C:104]([F:103])([F:117])[F:118])=[CH:109][CH:110]=5)[C:79]=4[CH3:86])[C:72]=3[CH:71]=2)[CH2:68][CH2:69]1)=[O:63]
Reactant: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: Cc1c(NC(=O)c2ccc(C(C)(O)C(F)(F)F)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12

Procedure:
Example 18 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 6 and Intermediate 8 with 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoic acid (WO2007/145834).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CO[CH:11]([NH:15][C:16]([NH2:18])=[O:17])[C:12](O)=[O:13]>Cl>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH:11]2[NH:15][C:16](=[O:17])[NH:18][C:12]2=[O:13])[CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COC(NC(N)=O)C(=O)O
Agent: Cl
Product: O=C1NC(=O)C(c2cc(Br)ccc2O)N1

Procedure:
To a 500-ml round-bottom flask equipped with a means for stirring and temperature control is added 0.55 mole (95.16 g) of p-bromophenol, 0.30 mole (44.44 g) of α-methoxyhydantoic acid, and 50 ml of concentrated HCl. The mixture is stirred at 50° C. for 17 hours. The water layer is then decanted, and the gum is washed with water several times. The resulting solid material is then crystallized from an ethanol-water solution to give the title compound having a melting point of 274° C. The structure is confirmed using C13 nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([OH:24])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(C2CCCN(C(=O)OCc3ccccc3)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
To a solution of 3-(3-hydroxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester (Example 11; 2.08 g, 6.39 mmol) in 15 mL dimethylformamide was added cesium carbonate (4.17 g, 12.78 mmol) and ethyl bromoacetate (1.42 mL, 12.78 mmol). The mixture was heated to 60° C. under N2 with stirring for 3 h and cooled to ambient temperature. The resultant brown suspension was diluted with 300 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 15% ethyl acetate/hexanes to yield 1.42 g (54%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid benzyl ester as a clear oil.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=O)[NH:8][C:7]=1[CH3:14])([OH:3])=[O:2].[N:15]1([C:21]2[CH:29]=[C:28]3[C:24]([CH2:25][C:26](=[O:30])[NH:27]3)=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[CH3:14][C:7]1[NH:8][C:9]([CH:12]=[C:25]2[C:24]3[C:28](=[CH:29][C:21]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:22][CH:23]=3)[NH:27][C:26]2=[O:30])=[C:10]([CH3:11])[C:6]=1[CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=C1Cc2ccc(N3CCOCC3)cc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(N4CCOCC4)ccc32)c(C)c1CCC(=O)O
Yield: 41.6 %

Procedure:
3-(2-Carboxyethyl)-2,4-dimethyl-5-formylpyrrole (3.3 g), 4 g 6-(morpholin-4-yl)-2-oxindole and 1.8 mL piperidine in 60 mL of ethanol were heated at 90° C. for 7 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The resulting solid was purified by chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 2.78 g (38% yield) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][CH2:17][OH:18])=[CH:11][C:10]=2[F:19])=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[N:24]#[C:25][NH2:26].[F:27][C:28]([F:34])([F:33])[S:29]([OH:32])(=[O:31])=[O:30]>C1COCC1>[OH:32][S:29]([C:28]([F:34])([F:33])[F:27])(=[O:31])=[O:30].[C:25](=[NH:24])([O:18][CH2:17][CH2:16][C:12]1[CH:13]=[C:14]([F:15])[C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]([F:23])([F:22])[F:21])[CH:4]=2)=[C:10]([F:19])[CH:11]=1)[NH2:26]
Reactant: N#CN
Reactant: OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: N=C(N)OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 31.3 %

Procedure:
To a solution of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3,5-difluorophenyl)ethanol (3.1 g, 8.79 mmol) and cyanamide (0.443 g, 10.55 mmol) in anhydrous THF (20 mL) was added trifluoromethanesulfonic acid (1.873 mL, 21.10 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 4 h. Purification via reverse phase Biotage then afforded the title compound as a white solid (1.5 g, 31.3% yield). LCMS: rt=3.64 min, [M+H+]=395
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC1(C)C(C)(C)OB[O:55]1.B(O[O-])=O.[Na+]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:55])[CH:16]=[C:15]([Cl:21])[C:14]=2[Cl:22])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C=Cc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Agent: O=BO[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(CCO)cc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,1-Dimethylethyl cyclopropyl[(2,3-dichloro-5-ethenylphenyl)methyl]carbamate (1 eq.) from the previous step, [Ir(COD)Cl]2 (0.025 eq.) and DPPB (0.05 eq.) were combined in THF (0.11 M). To this solution was then added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 eq.) and the resulting red solution was stirred at RT for 12 h. Finally, sodium perborate (0.1 M aqueous solution, 1 eq.) was added and the now black biphasic solution was vigorously stirred at RT for another 12 h. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a pale yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) EtOAc:Hex) afforded the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14].C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(N(CC)CC)C.C1C=CC=CC=1>[CH2:11]([NH:15][C:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1)=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: Oc1ccc(N=C=S)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCNC(=O)Oc1ccc(N=C=S)cc1

Procedure:
Three and eight-tenths grams (3.8 g.) (0.025 m.) of p-hydroxyphenylisothiocyanate was mixed with 2.5 g. (0.025 m.) of n-butylisocyanate in 50 mls. of benzene. To this mixture was added 3 drops each of triethylamine and dibutyltin dilaurate, and the mixture was allowed to stand at ambient temperature over night. After refluxing on the steam-bath for thirty minutes, the solvent was removed under vacuum by means of a rotary evaporator. The residue was slurried in n-hexane, filtered and air dried. There was obtained 5.4 grams of solid, m.p. 99°-102° C. The structure was confirmed by I.R.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:37][CH2:38]2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCC(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.81 g), triethylamine (1.4 cc) and 4-(4-chlorophenyl)piperidine (1.96 g) in toluene (30 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization firstly from boiling acetonitrile (12 cc) and then from boiling acetonitrile (17 cc), 2-{3-[4-(4-chlorophenyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 111° C.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C:7](N(OC)C)=[O:8])=[CH:4][CH:3]=1.[CH3:13][Mg]Br>O1CCCC1>[F:1][C:2]1[S:6][C:5]([C:7](=[O:8])[CH3:13])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(F)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
To a stirred solution of 5-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (12.34 g, 65.2 mmol) in tetrahydrofuran (163 mL) at 0° C. under nitrogen is added methyl magnesium bromide (3 M solution in tetrahydrofuran, 32.6 mL, 97.8 mmol) over a period of 25 minutes, while maintaining the internal temperature below 10° C. The cooling bath is removed and the solution is allowed to warm to room temperature over 1 hour. A saturated solution of ammonium chloride (200 mL) is added and the mixture is stirred for 10 minutes. The mixture is diluted with diethyl ether (200 mL) and the phases are separated. The aqueous phase is re-extracted with diethyl ether (2×150 mL) and the combined organic extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure (keeping the water bath below 25° C.) to give the crude title compound (9.70 g, 103%) as a pale amber liquid. 1H NMR (CDCl3) δ 2.47 (s, 3H), 6.53 (dd, J=1.2, 4.3 Hz, 1H), 7.38 (t, J=4.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), acetic anhydride (0.38 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].NC(N)=O>O.Cl>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Nc1cccc(F)c1F
Reactant: O=N[O-]
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: NNc1cccc(F)c1F
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
In each of two flasks, 775 mmol (100 g) of 2,3-difluoroaniline were added to 2 L of concentrated hydrochloric acid at -15° C. and treated dropwise with a solution of 852 mmol (58.9 g) of sodium nitrite in 500 mL of water. Ten minutes after the addition, the reaction was treated with 930 mmol (55.8 g) of urea. This was followed by rapid addition of a solution of stannous chloride dihydrate (968 mmol, 220 g) in 700 mL of concentrated hydrochloric acid precooled to -50° C. After 20 minutes, the solid from both reactions was filtered and combined. It was put into 3 L of 1M NaOH (aq) and extracted with 4×500 mL of ether. The extracts were combined, dried over MgSO4 and concentrated to afford 110 g of 2,3-difluorophenylhydrazine (763 mmol, 49%).