Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16]([I:17])[C:3]=12.CS(C)=[O:29]>[OH-].[Na+]>[I:17][C:16]1[C:3]2[C:2]([OH:29])=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:6]=[N:5][C:4]=2[N:14]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:15]=1
Reactant: CS(C)=O
Reactant: CN1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(CCn2nc(I)c3c(O)c(-c4ccccc4)nnc32)CC1
Temperature: 50 °C

Procedure:
A suspension of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (140 mg, 0.29 mmol) in DMSO (3 mL) and NaOH aqueous solution (4 M, 3 mL) was heated to 50° C. for 2.5 h. The mixture was left to cool to rt, then neutralised to pH 2-3 before loading on an SCX (10 g) cartridge. The cartridge was eluted with MeOH then CH2Cl2/MeOH (1:1) and finally the product was released with 10% methanolic ammonia (7 N) in CH2Cl2/MeOH (1:1). Evaporation of the solvent gave the title compound (100 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][O:57][C:58]1[N:63]=[CH:62][C:61]([C:64](O)=[O:65])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:64]([C:61]1[CH:62]=[N:63][C:58]([O:57][CH3:56])=[CH:59][CH:60]=1)=[O:65]
Reactant: COc1ccc(C(=O)O)cn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)cn1
Yield: 59.2 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (100 mg, 0.324 mmol) in DMF (5 ml) was added HOBT.H2O (49.7 mg, 0.324 mmol), HBTU (123 mg, 0.324 mmol), 6-(methyloxy)-3-pyridinecarboxylic acid (49.7 mg, 0.324 mmol) and DIPEA (0.170 ml, 0.973 mmol) and the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated in vacuo. The residue was dissolved in DCM (50 ml), transferred to a separating funnel and the solution was washed with NaHCO3 (5 ml), twice. The organic layer was dried with magnesium sulphate which was removed by filtration and the filtrate evaporated to dryness in vacuo. The residual oil was dissolved in 1:1 MeCN/DMSO (1.8 ml) and purified by MDAP in two batches. The fractions containing the desired product were combined and evaporated to dryness in vacuo to yield the title compound (85 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: OCCNCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 5, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and diethanolamine were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-hydroxy-ethyl)-amino]-ethanol as white semisolid, MS: 465(MH+, 1Br).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.[Cu]Br>[CH2:17]([NH:24][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccccc1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cccnc1NCc1ccccc1
Temperature: 100 °C

Procedure:
Potassium carbonate (4.82 g, 34.9 mmol) was added to a mixture of 2-chloronicotinic acid (5.0 g, 31.7 mol), benzylamine (3.47 ml, 31.7 mmol) and copper (I) bromide (450 mg, 3.17 mmol) in N,N-dimethylformamide (50 ml), and the reaction heated at 100° C. for 2 hours, then cooled. The resulting solid was filtered off and the filtrate evaporated under reduced pressure. The residue was partitioned between 4N sodium hydroxide solution (25 ml) and dichloromethane (25 ml) and the layers separated. The organic solution was extracted with water (2×), and the combined aqueous solutions, neutralised using concentrated hydrochloric acid. The resulting solid was filtered off, washed with cold water and dried in vacuo at 50° C., to afford the title compound, 1.6 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][OH:24])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:12]([CH2:23][O:24][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC1OCCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Yield: 90.3 %

Procedure:
A solution of [(6RS,7SR)-4-benzyl-6-(3,4-dichlorophenyl)-1,4-oxazepan-7-yl]methanol (1.63 g), triethylamine (0.741 mL), tert-butyldimethylsilyl chloride (738 mg) and 4-dimethylaminopyridine (catalytic amount) in DMF (10 ml) was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.93 g).
Reaction SMILES: [C:1](=[N:9][NH2:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C1([N:17]=[C:18]=[S:19])CCCCC1>CO>[C:1](=[N:9][NH:10][C:18]([NH2:17])=[S:19])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CC(=NN)c1ccccn1
Reactant: S=C=NC1CCCCC1
Solvent: CO
Product: CC(=NNC(N)=S)c1ccccn1
Yield: 46 %

Procedure:
A solution of 6.76 g (0.05 mol) of 2-acetylpyridine hydrazone in 10 ml of MeOH was treated with 7.2 g (0.05 mol) of cyclohexyl isothiocyanate and the solution was heated at reflux for 3 hours. The solution was chilled, and the crystals which formed were collected. Recrystallization of the product from 150 ml of MeOH afforded 6.40 9 (46%) of white needles of 2-acetylpyridine 4-cyclohexyl-3-thiosemicarbazone, mp 155° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)CNC1CCCCCC1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCCC1
Temperature: 25 °C

Procedure:
CBZ-L-Valine (10.05 g, 0.04 mol) was dissolved in CH2Cl2 (300 mL) and the following reagents were added in equal molar amounts in the stated order: 4-Dimethylaminopyridine, ethyl-N-(cycloheptyl)glycinate and WSCDI. Used additional 100 mL CH2Cl2 to wash down the reagents. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then 1N HCl and separated. The organic extract was washed with 1N HCl followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded the titled compound as an oil (11.2 g) which was used as is for saponification.
Reaction SMILES: [CH3:1][C@@H:2]1[C:8]2[C:9]([CH2:11][C@H:12]([CH3:13])[C:7]=2[CH2:6][C@H:5]([C:14]([CH3:16])=[CH2:15])[CH2:4][CH2:3]1)=O.C[C@@H]1[C@H]2C(=C(C)CC[C@@H](C(C)=C)C2)[C@H](O)C1.C[C@@H]1[C@H]2C(=C(C)CC[C@@H](C(C)=C)C2)[C@@H](O)C1>>[CH3:13][C@@H:12]1[C@H:7]2[C:8](=[C:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([C:14]([CH3:16])=[CH2:15])[CH2:6]2)[CH2:9][CH2:11]1
Reactant: C=C(C)[C@@H]1CC[C@H](C)C2=C(C1)[C@@H](C)CC2=O
Agent: C=C(C)[C@@H]1CCC(C)=C2[C@@H](C1)[C@@H](C)C[C@@H]2O
Agent: C=C(C)[C@@H]1CCC(C)=C2[C@H](O)C[C@H](C)[C@@H]2C1
Product: C=C(C)[C@@H]1CCC(C)=C2CC[C@H](C)[C@@H]2C1

Procedure:
GC-analysis: 15% α-bulnesene oxides, 1%/3-patchoulenone, 1.25% rotundone, 1.8% bulnesenone, 0.1% (1R,3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulen-1-ol (compound of formula I), 1.6% (1S,3S,3aS,5R)-3,8-dimethyl-5-(prop-1-en-2-yl)-1,2,3,3a,4,5,6,7-octahydroazulen-1-ol (compound of formula I).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20](=[O:37])[CH:21]([NH:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20](=[O:37])[CH:21]([NH:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]2)[CH2:10][CH2:9]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Reaction time: 8 h

Procedure:
4-(4-{2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoylamino}-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.1 mmole) was dissolved in 20 mL of methylene chloride and 1.6 mL of trifluoroacetic acid was added. Reaction stirred overnight, extrated with sodium bicarbonate, and used without further purification to afford the title compound: C13 NMR (100 MHz, CDCl3) 12.8, 18.9, 29.9, 34.1, 41.5, 43.2, 52.4, 53.7, 101.8, 105.6, 111.9, 112.1, 132.0, 137.1, 170.4, 171.5; MS 420.1 m/z (M+1).
Reaction SMILES: B.C1COCC1.[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:18]([C:19](=O)[CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:17][CH2:16][S:15][C:14]=2[CH:34]=1)([O-:9])=[O:8]>>[C:29]([O:28][C:26]([C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][N:18]1[CH2:17][CH2:16][S:15][C:14]2[CH:34]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=[CH:12][C:13]1=2)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1CCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
IM Borane in THF (17.18 mL, 17.18 mmol) was added to (S)-tert-butyl 1-(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)pyrrolidine-2-carboxylate (1.4 g, 3.44 mmol), and the resulting yellow solution was stirred at room temperature overnight (17 hours). The yellow solution was cooled to 0° C. and carefully quenched with MeOH (10 mL). The solution was concentrated, dissolved in MeOH (50 mL), and concentrated again to give a dark yellow residue. This residue was subjected to silica gel chromatography using the Biotage purification system (column: Silicycle 80 g; 20:80 EtOAc:hexanes gradient to 60:40 EtOAc:hexanes over 10 column volumes; flow rate=45 mL/min; collection wavelength: 254 nm). A yellow residue was obtained (550 mg, 40.7%). 1H-NMR (CDCl3) δ 7.96 (d, J=2.7 Hz, 1H), 7.87 (dd, J=2.7, 9.3 Hz, 1H), 6.68 (d, J=9.3 Hz, 1H), 3.86-3.82 (m, 2H), 3.57 (t, J=7.5 Hz, 2H), 3.24-3.10 (m, 2H), 3.05-2.96 (m, 3H), 2.75-2.63 (m, 1H), 2.52-2.41 (m, 1H), 2.15-2.04 (m, 1H), 1.97-1.78 (m, 3H), 1.44 (s, 9H); ESI-MS (m/z, %): 394 (MH+, 25), 338 (100).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1>S(=O)(=O)(O)O.O>[Br:5][C:6]1[CH:7]=[C:8]([Br:12])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Brc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add drop wise fuming nitric acid (101.40 mL) to a solution of 1,3-dibromo benzene (102.51 mL) in concentrated sulfuric acid (322.79 mL) and water (62.39 mL) at 0° C. Warm to RT and stir for 12 h. Pour the reaction on ice-water (1500 mL). Filter the resulting yellow solid under vacuum and dry to afford 178.46 g of the title compound. MS (ES+): m/z=281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[O:33])[NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nc(C2CCN(C(=O)Nc3ccccc3)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of 2-amino-4-(4-piperidinyl)quinazoline (100 mg, 0.44 mmol) obtained in Example 11(1) and triethylamine (133 mg, 1.3 mmol) in dichloromethane (50 ml) was added phenyl isocyanate (50 mg, 0.42 mmol) under a nitrogen atmosphere. The mixture was stirred for about 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by silicagel column chromatography (chloroform:methanol=99:1) to give the titled compound (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][CH:12]([F:27])[C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH2:22][C:23]2([F:26])[CH2:25][CH2:24]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH:12]([F:27])[F:11])=[N:14][CH:15]=1)[CH2:22][C:23]1([F:26])[CH2:25][CH2:24]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(CC1(F)CC1)c1cnc(C(F)F)nc1
Product: O=C(NCC(CC1(F)CC1)c1cnc(C(F)F)nc1)c1ccccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chlorobenzoic acid and 2-(2-(difluoromethyl)pyrimidin-5-yl)-3-(1-fluorocyclopropyl)propan-1-amine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=384.1, tR (minutes, Method F)=2.72. [α]D20=+21.30 (c=2.39 mg/mL,CHCl3)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:21]=[C:22]2[C@:33]3([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]3)[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:40]4[C:41]([F:46])=[N:42][CH:43]=[CH:44][CH:45]=4)[CH:31]=3)[O:26][C:23]2=[N:24][CH:25]=1.O>O1CCOCC1.CO.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:46][C:41]1[C:40]([C:30]2[CH:31]=[C:32]3[C@@:33]4([CH2:38][CH2:37][O:36][C:35]([NH2:39])=[N:34]4)[C:22]4[C:23](=[N:24][CH:25]=[C:20]([C:14]5[CH:13]=[CH:12][N:11]=[C:10]([F:9])[CH:15]=5)[CH:21]=4)[O:26][C:27]3=[CH:28][CH:29]=2)=[CH:45][CH:44]=[CH:43][N:42]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(-c3ccnc(F)c3)cc12
Temperature: 90 °C
Yield: 73.4 %

Procedure:
In a microwave vial, potassium phosphate (0.084 g, 0.394 mmol), PdCl2(AmPhos)2 (8.38 mg, 0.012 mmol), and 2-fluoropyridin-4-ylboronic acid (0.024 g, 0.171 mmol) were loaded. The (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.058 g, 0.131 mmol) was added as a solution in dioxane (2.5 mL). Water (1 mL) was added and argon gas was blown through the vessel, which was sealed and heated in a 90° C. oil bath for 1.5 h. The residue was taken up in 5% MeOH/DCM (60 mL) and the organic layer was extracted with dilute brine (2×6 mL), then was dried over sodium sulfate and concentrated. The residue was purified by chromatography (4.5-5.5% MeOH/DCM) to afford (S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (Example 60A; 44 mg). MS (m/z) 458 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm: 8.57 (d, 1H, J=2.5 Hz), 8.32 (d, 1H, J=5.3 Hz), 8.22 (d, 1H, J=4.7 Hz), 8.07 (d, 1H, J=2.3 Hz), 7.88 (m, 1H), 7.55 (m, 2H), 7.43 (m, 2H), 7.30 (m, 1H), 7.17 (s, 1H), 4.39 (br, 2H), 4.18 (m, 2H), 2.02 (m, 1H), 1.90 (m, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]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.[NH2:58][C:59]1[S:60][C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=1.Cl>O.C(OCC)(=O)C>[S:60]1[C:61]2[CH:67]=[CH:66][CH:65]=[CH:64][C:62]=2[N:63]=[C:59]1[NH:58][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1nc2ccccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3s2)cc1[N+](=O)[O-]
Yield: 43.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (50 mg, 0.15 mmol), triethylamine (0.060 mL, 0.44 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (98 mg, 0.22 mmol), and 2-aminobenzothiazole (33 mg, 0.22 mmol) in N,N-dimethylformaniide (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded N-benzothiazol-2-yl-3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-propionamide (31 mg, 45%) as a pale yellow foam: mp 108-113° C. (foam to gel); EI-HRMS m/e calcd for C22H23N3O5S2 (M+) 473.1079, found 473.1077.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(Cl)Cl>[N:38]1([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=4)/[N:13]([C@H:14]4[CH2:15][CH2:16][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:19]4)[C:12]=3[CH:26]=2)[CH:42]=[N:41][CH:40]=[N:39]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(Cn4cncn4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed at reduced pressure, and the residue was dried in vacuo for 5 minutes. The residue was resuspended in ACN (2 mL), cooled to 0° C., and 1H-1,2,4-triazole (153 mg, 2.210 mmol), potassium carbonate (305 mg, 2.210 mmol), and sodium iodide (33.1 mg, 0.221 mmol) were added. The reaction was stirred at RT. After 16 hours, the solvent was removed, and the residue was partitioned between water and DCM. The aqueous layer was neutralized (pH approximately 8) with 2 N aqueous HCl and extracted with DCM. The combined organic layers were concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide (E)-N-(6-((1H-1,2,4-triazol-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (35 mg, 31% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.80 (s, 1H), 8.69 (s, 1H), 8.33 (dd, J=6.0, 8.6 Hz, 2H), 7.95 (s, 1H), 7.76 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.15, (d, J=8.2 Hz, 1H), 5.45 (s, 2H), 4.78 (brs, 1H), 4.02-4.14 (m, 1H), 2.74-2.85 (m, 2H), 2.54 (brs, 1H), 2.10-2.13 (d, J=12.8 Hz, 2H), 1.69-1.76 (m, 2H), 1.59-1.62 (m, 2H), 1.11 (d, J=6.6 Hz, 6H). MS, m/z (C27H30FN7O2): calcd, 503.2; found, 503.7 [M+H].
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:30]=[N:31][C:32]([CH3:36])=[C:33](Br)[CH:34]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3([C:26]([NH:28][C:29]4[CH:30]=[N:31][C:32]([CH3:36])=[C:33]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=5)[CH:34]=4)=[O:27])[CH2:25][CH2:24]3)=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(S(N)(=O)=O)c1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-(3-sulfamoylphenyl)pyridin-3-yl)cyclopropanecarboxamide was prepared from 3-sulfamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][Si:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([Cl:8])Cl>C(OCC)C.II>[Cl:8][Si:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: ClCCC[Si](Cl)(Cl)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: Cl[Si]1(c2ccccc2)CCC1
Reaction time: 48 h
Yield: 60.2 %

Procedure:
A dry 1 L three neck round bottom flask equipped with a mechanical stirrer, dropping funnel, and condenser with nitrogen inlet system was charged with 18.3 g (0.75 mole) magnesium powder and 250 ml anhydrous diethyl ether. The magnesium was activated by the addition of 200 mg iodine. And then 50.7 g (0.20 mole)(3-chloropropyl)phenyldichlorosilane in 100 ml diethyl ether was added dropwise over 40 mins. at room temperature. The mixture was stirred for an additional 48 h and 200 ml anhydrous diethyl ether was added. The magnesium chloride and excess magnesium was filtered under nitrogen. The solid was washed with three portions of ether. The solvent was removed by the distillation and the product was distilled by reduced pressure. 22 g of 1-chloro-1-phenyl-1-silacyclobutane b.p. 83°-85° C./2 mm Hg was obtained.