Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([SH:9])([CH3:8])[CH3:7].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>C(O)C>[C:6]([S:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1)([CH3:8])([CH3:7])[CH3:5]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)S
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)Sc1ccc(C#N)cn1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Add sodium ethoxide (12 mL of 21% w/v in ethanol, 36 mmol) to a solution of 2-methyl-2-propanethiol (4.06 mL, 36 mmol) in anhydrous ethanol (90 mL) at 0° C. under nitrogen atmosphere. Stir the solution and allow it to warm to room temperature over 30 min. Add 6-chloronicotinonitrile (5 g, 36 mmol) and then heat the reaction to reflux overnight. Cool to room temperature, add saturated aqueous NaHCO3 and concentrate in vacuo. Extract into EtOAc or dichloromethane and wash with brine. Dry over MgSO4 and concentrate in vacuo to give the desired intermediate as orange crystals (6.31 g, 91%). MS (ES+) m/z: 193 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.CN([CH:31]=[O:32])C>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([CH:31]=[O:32])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cnccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution (50 ml) of 4-chloropyridine (25.0 g, 0.22 mol) in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (300 ml) of lithium diisopropylamide prepared from a solution (179 ml, 0.29 mol) of 1.6 M n-butyllithium in hexane and diisopropylamine (33.4 g, 0.33 mol) under an argon atmosphere at −78° C. After stirring for 30 min., DMF (19.3 g, 0.26 mol) was added and the mixture was gradually heated to room temperature. The reaction mixture was extracted with ethyl acetate (200 ml)-5% NH4Cl aq. (300 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure to give a crude title compound (27 g, 86%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][N:29]([CH3:44])[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:35]2[S:40](Cl)(=[O:42])=[O:41].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:40]([C:35]3[C:36]4[C:31](=[C:30]([N:29]([CH3:44])[CH3:28])[CH:39]=[CH:38][CH:37]=4)[CH:32]=[CH:33][CH:34]=3)(=[O:42])=[O:41])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Sc2ccc(OS(=O)(=O)c3cccc4c(N(C)C)cccc34)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (167 mg, 0.94 mmol) was reacted with 5-Dimethylamino-naphthalene-1-sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL of CH2Cl2 with N,N-diisopropylethylamine (0.530 mL, 410 mmol) for 22 h. Washed with water and dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (35 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H) 2.86 (s, 6H) 6.65 (d, J=6.99 Hz, 1H) 6.76 (d, J=9.19 Hz, 2H) 6.87 (d, 2H) 7.16 (d, J=8.82 Hz, 1H) 7.34 (d, J=7.72 Hz, 1H) 7.53-7.62 (m, 2H) 7.69-7.79 (m, 3H) 7.97 (d, J=7.35 Hz, 1H) 8.22 (d, J=8.82 Hz, 1H) 8.50 (d, J=6.99 Hz, 1H) 8.60 (d, J=8.46 Hz, 1H) 8.82 (d, J=8.82 Hz, 1H); MS 1H) 8.50 (d, J=6.99 Hz, 1H) 8.60 (d, J=8.46 Hz, 1H) 8.82 (d, J=8.82 Hz, 1H); MS (DCI NH3+) m/z 611 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O-:19])=[O:18])=[CH:5]2.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>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:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2
Reactant: O=C([O-])C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccc(F)cc3)c2OC1C(F)(F)F
Temperature: 100 °C
Yield: 34 %

Procedure:
To 0.400 g (0.428 mmole) of Wang resin 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 50 mg (0.043 mmole) tetrakis(triphenylphosphine)palladium(0), 0.180 g (1.285 mmole) 4-fluorophenylboronic acid, 0.857 mL K2CO3 (2M soln degassed), and 4 mL degassed DMF. The reaction mixture was heated to 100° C. for 18 hr. The reaction mixture was transferred and washed as follows: DMF (×5), H2O (×5), MeOH (×5), and CH2Cl2 (×5). The resin was treated with 2 mL (TFA:CH2CL2, 1:1) for 30 minutes. The filtrate was collected and treatment was repeated. The resin was washed with CH2Cl2 (×2) and all filtrates were combined and concd. The resulting oil was purified using reverse phase chromatography to afford 0.055 g (34%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 5.66 (q, 1H, J=6.8 Hz), 7.10-7.15 (m, 2H), 7.26 (d, 1H, J=2.4 Hz), 7.37 (d, 1H, J=2.4 Hz), 7.42-7.47 (m, 2H), 7.90 (s, 1H); MS (ES+) 373 (M+1, 100); HRMS (ES−) m/z calcd for (C17H9O3ClF4) 371.0093, found 371.0067.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[C:29]4[CH:28]=[CH:27][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:25][C:24]=4[C:8]4[CH:9]=[C:10]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:11]=[C:12]([C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1)[C:7]3=4.C([Li])CCC.[B:41]([O:46]C)(OC)[O:42]C>C1COCC1.C1CCCCC1>[CH3:16][C:13]1([CH3:17])[C:12]2[C:7]3=[C:8]([C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:27]=[CH:28][C:29]=4[N:6]3[C:5]3[CH:4]=[CH:3][C:2]([B:41]([OH:46])[OH:42])=[CH:15][C:14]1=3)[CH:9]=[C:10]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:11]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2cc(Br)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2cc(B(O)O)ccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32
Temperature: 25 °C

Procedure:
133 g (259 mmol) of 10-bromo-8,8-dimethyl-3,6-diphenyl-8H-indolo-[3,2,1-de]acridine are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[CH:44]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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(Cl)Cl>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[CH:39][C:40]([N:43]4[C:47](=[O:48])[N:46]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[N:45]=[CH:44]4)=[CH:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2ccc(-n3cnn(COCC[Si](C)(C)C)c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncn(-c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2)c1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of compound 2b (100 mg, 0.229 mmol), compound 82c (115 mg, 0.275 mmol), PdCl2(dppf)-DCM (5.6 mg, 0.0069 mmol), and Argon-degassed aqueous 2M Na2CO3 (0.573 mL, 1.15 mmol) in Argon-degassed 1,4-dioxane (4 mL) was further degassed with Argon for 3 min and then stirred at 90° C. for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to a brown oil which was purified by flash column chromatography on silica gel (20-100% EtOAc-DCM), followed by a second purification by flash column chromography for mixed fractions (0-80% EtOAc-DCM), to afford compound 83a as a pale yellow solid. Mass spectrum (LCMS, ESI pos.): Calcd. for C35H38N8O3Si, 647.3 (M+H). found 647.7.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]2[O:9][N:10]=[C:11]([OH:12])[C:6]2=[CH:5][CH:4]=1.[N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:16]=[O:17]>C1COCC1>[CH2:18]([NH:15][C:16]([N:10]1[C:11](=[O:12])[C:6]2[C:7](=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)[O:9]1)=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCN=C=O
Reactant: Oc1noc2nc(C(F)(F)F)ccc12
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1oc2nc(C(F)(F)F)ccc2c1=O

Procedure:
In analogy to example 1c, 47 mg (0.23 mmol) of 6-trifluoromethylisoxazolo-[5,4-b]pyridin-3-ol were reacted with 34.9 mg (0.27 mmol) of 1-isocyanatohexan in THF. Yield: 15 mg (20%), M+H+: 332.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18]I.Cl>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(OCc2ccccc2)c1
Reactant: II
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1cc(I)c(O)c(OCc2ccccc2)c1
Temperature: 77.5 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of 3-Benzyloxy-4-hydroxy benzaldehyde (15 g, 0.065 mol) and Iodine (17.54 g, 0.13 mol) was added 3.2% NaOH solution (150 ml). The reaction mixture was stirred at 75-80° C. for 8 h. The reaction mixture was cooled to room temperature and concentrated hydrochloric acid was added and the solid was filtered. Then the compound was recrystalized with isopropanol. The solid was filtered and dried to give 3-benzyloxy-4hydroxy-5-Iodo benzaldehyde (18.40 g, 79%). TLC: Ethyl acetate:light petroleum (2:5), Rf=0.4; 1H NMR (CDCl3, 200 MHz): δ 5.20 (s, 2H), 7.23-7.45 (m, 6H), 7.8 (d, J=1.42 Hz, 1H), 9.73 (s,1H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[C:7]([N+:29]([O-:31])=[O:30])[CH:6]=1)(=[O:4])=[O:3].Cl>O1CCOCC1>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:21][S:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:13][C:14]([OH:16])=[O:15])=[C:7]([N+:29]([O-:31])=[O:30])[CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1

Procedure:
A mixture of Example 122D and 4M HCl in 1,4-dioxane (10 mL) was stirred at 50° C. for 5 hours and concentrated to provide the desired product. MS (ESI(+)) m/e 412 (M+H)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=O.[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21]>C(O)(=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:26]([CH2:25][CH2:24][NH:23][C:20](=[O:22])[CH3:21])[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)NCCN
Reactant: O=C(CCC1OCCO1)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(C(F)(F)F)cc1
Yield: 78.1 %

Procedure:
3-(1,3-Dioxolan-2-yl)-4'-(trifluoromethyl)-propiophenone (6.4 g) was added under argon and while stirring to a solution of 4.8 g of N-acetylethylenediamine in 70 ml of acetic acid. The reaction mixture was refluxed overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 70 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 9.4 g of yellow-brown solid was chromatographed on 500 g of silica gel with ethyl acetate as the eluent. 5.4 g (78%) of N-[2-[2-[4-(trifluoromethyl)phenyl]-pyrrol-1-yl]ethyl]acetamide were isolated as a yellow amorphous solid. MS: m/e=296 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: COc1cccc(C#N)c1N
Product: COc1cccc(C#N)c1NC(=O)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 53a from 2-amino-3-methoxybenzonitrile and benzoyl isocyanate as a light orange solid (280 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ3.89 (s, 3H), 7.42 (t, J=3.2 Hz, 2H), 7.46 (d, J=3.6 Hz, 1H), 7.54 (t, J=8 Hz, 2H), 7.66 (t, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 10.55 (s, 1H), 11.32 (s, 1H). MS 295 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH2:16][CH3:17])[C:14](=[O:18])[C:13]([CH3:20])([CH3:19])[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([CH2:16][CH3:17])[C@H:14]([OH:18])[C:13]([CH3:20])([CH3:19])[C:12]2=[O:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1C

Procedure:
Using 2-chloro-4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)-3-methylbenzonitrile (310 mg) and lithium tri(sec-butyl)borohydride-THF solution (1.53 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 211 mg, 68%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1Nc2cc(Br)ccc2C12CCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Temperature: 105 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6′-bromospiro[cyclopentane-1,3′-indolin]-2′-one (preparation 2, 0.650 g, 2.44 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (WO200700565, 0.96 g, 3.66 mmol), 1,4-dioxane (25 mL) and a 2M aqueous cesium carbonate solution (3.7 mL, 7.4 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.12 g, 0.15 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100-110° C. After 20 hours, the mixture was cooled and partitioned between water and ethyl acetate. The combined organic extract was dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (95:5 dichloromethane/methanol) gave the title compound (0.64 g, 81%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1>>[CH3:10][C:5]1[C:4]([C:1]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)([OH:3])[CH3:2])=[C:8]([CH3:9])[O:7][N:6]=1
Reactant: Brc1ccsc1
Reactant: CC(=O)c1c(C)noc1C
Product: Cc1noc(C)c1C(C)(O)c1ccsc1

Procedure:
The title compound was prepared following the general method of Example 4 but starting with 4-acetyl-3,5-dimethylisoxazole and 3-bromothiophene. M.p. 93.5°-95° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](O)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].B>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 1-(4-nitrophenyl)piperidine-4-carboxylic acid (1.0 g, 4.0 mmol) in tetrahydrofuran (14 mL) is added borane.tetrahydrofuran complex (1.8 M, 7 mL, 13 mmol). After completion of the dropwise addition, the coolant is removed. The mixture is stirred overnight at room temperature and re-cooled to 0° C. in an ice-water bath. Sodium hydroxide solution (1M, 6 mL) is added dropwise. The basic mixture is neutralized by the addition of saturated aqueous ammonium chloride solution. The mixture is extracted 3× with ethyl acetate, and the combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give [1-(4-nitro-phenyl)-piperidin-4-yl]-methanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][C:14](=[O:16])[CH3:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Br[CH2:18][C:19]#[N:20]>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:13]([CH2:18][C:19]#[N:20])[C:14](=[O:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(=O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Product: CC(=O)C(CC#N)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a 300 mL reaction flask was added 2.4 g (59.3 mmole) sodium hydride (60% dispersion in oil) and 10 mL hexanes. The hexanes were removed by pipette and replaced by 60 mL dry tetrahydrofluran (THF). The suspension was cooled to -15° C. and a solution of 12.0 g (51.6 mmole) 4-chlorophenylsulfonyl acetone in 50 mL THF was added via addition funnel over 20 minutes maintaining the reaction temperature below -12° C. The resulting yellow solution was removed from the cold bath and stirred at room temperature for 30 min. The solution was recooled to -5° C. and 3.8 mL (54.1 mmole) bromoacetonitrile was added dropwise via addition funnel. After 5 min, the reaction mixture was removed from the cold bath and stirred at room temperature overnight. The reaction was quenched with 1 mL of saturated ammonium chloride and transferred with 100 mL of dichloromethane to a separatory funnel containing 100 mL brine. The organic layer was separated and the aqueous layer was back extracted once with 50 mL more dichloromethane. The combined organics were then dried with sodium sulfate, filtered, concentrated, and chromatographed through a bed of silica gel using 1:1 hexane: dichloromethane. Isolation gave 8.2 g (59% yield) of 3-(4-chlorophenylsulfonyl)-4-cyanobutan-2-one, a yellow oil that was 90% pure by HPLC. 1H NMR (CDCl3) indicated desired product as the major component: δ7.6 (m, 4H), 4.42 (dd, 1H), 2.78 (m, 2H), 2.48 (s, 3H).
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[C:12]2[N:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[K+].[Br-]>>[F:21][C:20]([F:23])([F:22])[C:18]1[CH2:17][N:13]2[CH:14]=[CH:15][C:16]3[C:11]([CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:1]=3)=[C:12]2[N:19]=1
Reactant: CCOC(=O)C(=Cc1cccn2cc(C(F)(F)F)nc12)N=[N+]=[N-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)c1cc2c3n(ccc-2n1)CC(C(F)(F)F)=N3

Procedure:
From 6e (yield: 79%); mp 230-231° C.; IR (KBr) 3283, 1686, 1264 cm−1; 1H NMR (400 MHz, acetone-d6) δ 1.43 (t, 3H, J=7 Hz), 4.43 (q, 2H, J=7 Hz), 7.33 (d, 1H, J=7 Hz), 7.55 (s, 1H), 8.33 (s, 1H), 8.37 (d, 1H, J=7 Hz), 11.74 (brs, 1H); 13C NMR (100 MHz, acetone-d6) δ 14.6, 61.5, 104.3, 107.9, 114.2, 114.8, 124.4 (d, 1JF-C=266 Hz), 125.3, 127.9, 133.8 (q, 2JF-C=37 Hz), 134.4, 143.1; 161.4; MS m/z 297 (M+, 66), 251 (100), 223 (27), 154 (14). Anal. Calcd for C13H10F3N3O2: C, 52.53; H, 3.39; N, 14.14. Found: C, 52.78; H, 3.46; N, 14.02.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31](N(C)C2C=CC=CN=2)=[O:32])[C:13]1=[O:41])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:42]1([Mg]Cl)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:32])[C:13]1=[O:41])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: Cc1cccc2c1N(CC(=O)N(C)c1ccccn1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc2c1N(CC(=O)C1CCCCC1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-[N-methyl-N-(2-pyridyl)amino]carbonylmethyl-1H-1,4-benzodiazepin-2-one (400 mg) in tetrahydrofuran (4 ml) was added cyclohexyl magnesium chloride (1.08 ml) under stirring, at 0° C. The mixture was stirred for twenty minutes under the same conditions and at room temperature overnight. Ethyl acetate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The separated organic layer was washed with 0.1N aqueous hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and brine successively and dried under magnesium sulfate. The solvent was removed in vacuo to afford a residue, which was subjected to column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (20:1) to give (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-1-cyclohexylcarbonylmethyl-2,3-dihydro-9-methyl-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([NH:6][NH:7][C:8]([S-:10])=[S:9])=O.[K+].S(=O)(=O)(O)O>C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][C:4]1[S:9][C:8]([SH:10])=[N:7][N:6]=1
Reactant: O=C(CCO)NNC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCCc1nnc(S)s1
Yield: 24.7 %

Procedure:
Potassium 3-(3-hydroxypropionyl)dithiocarbazate (12 g) was added bit by bit to a mixture of conc. sulfuric acid (15 ml) and ethyl acetate (75 ml) at 0° to 5° C. over 15 minutes. The mixture was stirred for an hour at the same temperature. The reaction mixture was poured into ethyl acetate (800 ml), and the organic phase washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily residue. Petroleum ether was added thereto to solidify and the solid substance was washed with benzene to give 5-(2-hydroxyethyl)-1,3,4-thiadiazole-2-thiol (2.2 g). m.p. 101° to 103° C.