Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[F:12][C:13]([F:23])([F:22])[C:14]1[N:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:17][CH2:16][C:15]1[C:14]([C:13]([F:23])([F:12])[F:22])=[N:21][CH:20]=[CH:19][CH:18]=1)=[S:11]
Reactant: N#Cc1cccnc1C(F)(F)F
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: FC(F)(F)c1ncccc1CNC(=S)Nc1cccc(Cl)c1Cl
Yield: 95 %

Procedure:
Prepared in 95% yield from 2,3-dichlorophenylisothiocyanate and the product of Example 203A according to the procedure described for Example 153B. MS (ESI+) m/z 379.9 (M+H)+; 1H NMR (CDCl3) δ 5.11 (d, J=5.4 Hz, 2H), 6.38 (br s, 1H), 7.15-7.28 (m, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.34-7.38 (m, 1H), 7.44 (d, J=7.8, 1.7 Hz, 1H), 7.51 (dd, J=5.1, 4.7 Hz, 1H), 7.65 (br s, 1H), 8.18 (d, J=7.5 Hz, 1H), 8.63 (d, J=4.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:8]([N+:14]([O-])=O)=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=2[NH2:14])[CH:6]=1
Reactant: Cc1cn(-c2cccc(N)c2[N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: Cc1cn(-c2cccc(N)c2N)cn1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To a solution of 3-(4-methyl-imidazol-1-yl)-2-nitro-phenylamine (CXXIX) in methanol was added with 5% Pd/C. The combination was stirred under a hydrogen filled balloon at 40° C. for 6 hours. The solution was then filtered through a pad of Celite. The filtrate was concentrated in vacuo to get 3-(4-methyl-imidazol-1-yl)-benzene-1,2-diamine (CXXX). 1H NMR (CDCl3, 400 MHz) δ ppm 2.17 (s, 3H), 6.54 (m, 1H), 6.80 (m, 1H), 6.97 (m, 1H), 7.28 (m, 1H), 7.56 (m, 1H).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Oc1ccc(Br)cc1
Product: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 2-chloro-1H-benzo[d]imidazole (10 g), 4-bromophenol (56.7 g) and TEA (45.5 mL) was stirred at 150° C. overnight. The mixture was quenched with water at room temperature and extracted with AcOEt. The extract was washed with 1 M NaOH aqueous solution, dried over Na2SO4, and concentrated under reduced pressure. The precipitate was crystallized from AcOEt/hexane to give the title compound (11.9 g).
Reaction SMILES: Br[C:2]1[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH:7]=[CH:6][CH:5]=[C:4]3[CH:3]=1.BrBr>>[CH2:3]1[C:4]2=[C:13]3[C:8](=[CH:7][CH:6]=[CH:5]2)[CH:9]=[CH:10][CH:11]=[C:12]3[CH2:2]1
Reactant: BrC1=Cc2cccc3cccc1c23
Agent: BrBr
Product: c1cc2c3c(cccc3c1)CC2

Procedure:
After the reaction solution was cooled, separated potassium bromide was removed by filtration, methanol was distilled, washed 3 times with water, and the benzene solution was concentrated and dropwise added into cold acetone (0°~-10° C.), to obtain reprecipitate of 140 g of condensed bromoacenaphthylene. Elemental analysis showed that the composition of the condensate corresponded to (C12H4.4 Br2.7)m and the yield from acenaphthene was 76.8%.
Reaction SMILES: [N:1]1([C:10](=[O:22])[C:11](N2C3C=CC=CC=3N=N2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.Cl.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[N:28][C:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:34]=2[CH:35]=1.CCN(CC)CC>C1COCC1>[N:1]1([C:10](=[O:22])[C:11]([N:32]2[CH2:31][CH2:30][C:29]3[N:28]=[CH:27][C:26]([C:25]([F:36])([F:24])[F:37])=[CH:35][C:34]=3[CH2:33]2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: O=C(C(=O)n1nnc2ccccc21)n1nnc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C(=O)n1nnc2ccccc21)N1CCc2ncc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a suspension of 1,2-bis-benzotriazol-1-yl-ethane-1,2-dione (0.100 g, 0.342 mmol) in THF (3.4 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine monohydrochloride (0.082 g, 0.342 mmol) and the reaction mixture was stirred at ambient temperature for about 4 h. Et3N (0.05 mL, 0.34 mmol) was added and stirring was resumed for about 1 hour. The reaction mixture was concentrated in vacuo and the residue triturated from hot iPrOAc. The solid was removed by filtration and the filtrate concentrated in vacuo then dissolved in EtOAc (10 mL), washed with 1N aq NaOH (2×5 mL), and saturated aqueous NaHCO3 (10 mL). The organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide 1-benzotriazol-1-yl-2-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-ethane-1,2-dione as an orange oil (0.056 g, 0.15 mmol). The crude material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].[Cl-].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]#[N:24])=[CH:19][CH:18]=1>O.C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH2:9])[N:5]=[C:6]([NH2:8])[C:7]=1[N:24]=[N:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: N#[N+]c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=Nc2ccc(Cl)cc2)c(Cl)n1
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a suspens-ion of 4-chloro-2,6-diaminopyrimidine (21.68 g, 0.150 mol) in water (750 ml) and acetic acid (750 ml) was added sodium acetate (300 g). Solution occurred after stirring for 20 minutes, and then the solution of 4-chlorobenzenediazonium chloride (0.166 mol) was added with cooling over 30 minutes at a rate that kept the reaction at 18°. The reacton was stirred overnight at room temperature, and the orange crystals were filtered, washed with water (4×400 ml), and dried in vacuo to give 17.6 g of 6-chloro-5-[(4-chlorophenyl)azo]-2,4-pyrimidinediamine. The mother liquors were cooled to 5° for 20 hours, and the crystals were collected and dried in vacuo to give 6.94 g of additional 6-chloro-5-[(4-chlorophenyl)azo]-2,4-pyrimidineadiamine.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:36])(=[O:35])[NH2:34])[CH:28]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:37]=[C:26]([C:27]4[CH:28]=[C:29]([S:33]([NH2:34])(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (MeOH/diethyl ether) as an off-white solid (175 mg, 70%). MS (ISP) 500.3 [(M+H)+]; mp 326° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=2)[N:15]=1.[C:28](=[O:30])=[O:29]>C1COCC1>[Cl:13][C:14]1[C:23]([C:28]([OH:30])=[O:29])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]([F:26])([F:25])[F:27])[CH:20]=2)[N:15]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)ccc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(C(F)(F)F)ccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 1.54 ml (11.0 mmol) diisopropylamine in THF (38 ml) was cooled to 0° C. 6.9 ml (1.6 M in hexane, 11.0 mmol) n-BuLi were added dropwise at this temperature and then the mixture was stirred for 30 min at −78° C. Then a solution of 2.31 g (10.0 mmol) 2-chloro-6-(trifluoromethyl)quinoline in THF (12 ml) was added dropwise at −78° C. and the mixture was stirred for a further 30 min at −78° C. Then the reaction solution was poured onto finely dispersed dry ice. After heating to RT the mixture was concentrated to small volume under vacuum and the residue was taken up with water. It was made alkaline with a 1N aqueous NaOH solution and then washed with ether. Then it was acidified with a 10% aqueous hydrochloric acid and extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 198 mg (0.7 mmol, 72%) 2-chloro-6-(trifluoromethyl)quinoline-3-carboxylic acid were obtained as residue.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=1
Reactant: Cc1sc2cc(CCCCO)ccc2c1-c1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Product: Cc1sc2cc(CCCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 21.1, the 4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butan-1-ol was treated with methanesulfonic acid chloride to yield the Methanesulfonic acid 4-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-butyl ester as yellowish oil, MS: 442 (M+).
Reaction SMILES: [CH:1]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13](O)[CH:14]=[CH:15][CH:16]=1>>[Br:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][CH:12]=1)[O:9][CH2:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(Br)c1
Reactant: OCC1CCCCCC1
Product: Brc1cccc(OCC2CCCCCC2)c1

Procedure:
Cycloheptylmethanol was coupled with 3-bromophenol following the method used in Example 10. After concentration under reduced pressure, hexanes was added. The mixture was stirred and sonicated then the precipitate was removed by filtration and the solids washed with hexanes. The combined filtrates were concentrated under reduced pressure. Purification by flash chromatography (10 to 50% EtOAc-hexanes gradient) gave ((3-bromophenoxy)methyl)cycloheptane. (Yield 1.0697 g, 56%): 1H NMR (400 MHz, CDCl3) δ 7.12 (t, J=8.4, 1H), 7.06-7.04 (m, 2H), 6.82 (dq, J=8.0, 1.2, 1H), 3.70 (d, J=6.4, 2H), 1.91-1.98 (m, 1H), 1.81-1.88 (m, 2H), 1.42-1.72 (m, 8H), 1.24-1.34 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:15])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc(Br)cc2)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccc(Br)cc2)nc1
Temperature: 25 °C
Yield: 110.1 %

Procedure:
A mixture of 0.248 g of 2-(p-bromophenyl)-5-methyl-pyridine, 0.196 g of N-bromosuccinimide, 20 mg of dibenzoyl peroxide and 5 ml of carbon tetrachloride was heated to reflux for 2.5 hours while gassing with nitrogen. The reaction mixture was subsequently left to cool to room temperature and suction filtered. The residue was rinsed with carbon tetrachloride. The filtrate was concentrated in a vacuum, there being obtained 0.360 g of crude 2-(p-bromophenyl)-5-bromomethyl-pyridine as brownish crystals.
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ncc(CO)cc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.7 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of dimethylformamide was added a solution of 0.9 g. of 50% sodium hydride in 6 ml. of dimethylformamide. The mixture was stirred at room temperature for 3 hours and to the solution was added 1.25 g. of benzyl chloride and additional stirring was continued overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[N:28][C:29]#[N:30])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:34]#[N:35])[C:14]3=[N:28][C:29]#[N:30])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: N#CN=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#CN=C1N(C#N)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)-phenyl)imidazolidin-2-ylidene)cyanamide [prepared from Example 203] (15.0 mg, 0.033 mmol) in 1,4-dioxane (0.5 mL) is treated with excess BrCN and K2CO3. The reaction mixture is heated at 100° C. for 2 h, cooled, then quenched with H2O (5 mL) and extracted with EtOAc (3×3 mL). The combined organics are evaporated en vacuo and purified by preparatory LC/MS followed by preparatory TLC to provide the title compound; HPLC-MS calculated for C24H15ClF3N5O (M+H+) 482.1, found 482.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([O:34][CH3:35])(=[O:33])[C@H:30]([CH3:32])O.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C@H:30]([CH3:32])[C:29]([O:34][CH3:35])=[O:33])=[CH:3][C:2]=1[CH3:1]
Reactant: COC(=O)[C@H](C)O
Reactant: Cc1cc(O)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)Oc1ccc(Cl)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-chlorophenol (10.0 g, 69 mmol), triphenylphosphine (1.3 eq, 22 g), (S)-methyl lactate (1.3 eq, 9.4 mL) in DCM (230 mL) at 0° C. was added DEAD (1.2 eq, 13 mL) over 1 min. Reaction warmed to rt overnight. The mixture was then filtered through a pad of silica gel and concentrated. The residue was purified via flash chromatography eluting with 10% EtOAc/hexanes to provide the product as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH2:11])(=[O:10])[CH:8]=[CH2:9]>CCO>[N:1]1([CH2:9][CH2:8][C:7]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(N)=O
Reactant: C1CCNCC1
Solvent: CCO
Product: NC(=O)CCN1CCCCC1
Yield: 75 %

Procedure:
A solution of piperidine, 4-(diphenylmethylene) (0.10 mole) and acrylamide (8.95 g, 0.062 mole) in EtOH (50 ml) was refluxed overnight. This reaction mixture was filtered and concentrated. The resulting while solid residue was dissolved in CHCl3, washed with H2O (3×150 ml), dried (Na2SO4) and the solvent removed to give thick yellow oil. Crystallization from CH2Cl2 -i-Pr2O afforded 29.01 g (75%) of 1-piperidinepropanamide, 4-(diphenylmethylene)-; mp 105°-7° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[N:29][C:28]=1[OH:41]>C1COCC1>[Br:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:38])=[O:39])=[CH:34][CH:35]=2)[CH:30]=[N:29][C:28]=1[OH:41]
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccc2c(Br)c(O)ncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)c(O)ncc3c2)cc1
Reaction time: 0.25 h

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (655 mg, 2.97 mmol) was added THF (6940 μl) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (3185 μl, 3.19 mmol), faster than drop wise. After 15 mins of stirring, a solution of 4-bromo-3-hydroxyisoquinoline-7-sulfonyl chloride (685 mg, 2.124 mmol) in THF (4 mL) was added drop wise (with 1 mL THF wash). The mixture was stirred for 1.5 hr (ice melt), LCMS indicated complete conversion to the desired product. The solution was added to ice, diluted with EtOAc and extracted with water and EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 60% EtOAc in hexane, to provide 4-bromo-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide. m/z (ESI) 506.0 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:21][C@H:16]1[N:15]([C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)[N:4]=2)[CH2:20][CH2:19][N:18]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH2:17]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CN(c2ccc(C#N)cc2)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 120 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a stirred solution of 1-Methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (1.50 g, 5.24 mmol) in dimethyl sulufoxide (10.0 ml) was added 4-fluorobenzonitrile (1.27 g, 10.5 mmol), potassium carbonate (2.90 g, 21.0 mmol), and the reaction mixture was stirred for 12 hours at 120° C. The reaction was quenched with water, the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. After removal of the solvent, the precipitate was filtered, washed with ether, and dried to give 4-[(3R)-3-Methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (1.70 g, 4.39 mmol, 84%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[NH:27]([C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)=[O:30])[NH2:28]>>[NH:27]([C:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1)=[O:30])[NH2:28]
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: NNC(=O)c1ccc(C=O)cc1
Product: NNC(=O)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 230 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-hydrazinylcarbonylbenzaldehyde. [M+H]+ calcd for C25H24N6O2: 441.21; found: 441.51.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17]>C1COCC1>[N+:1]([C:4]1[C:5]([CH3:13])=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][NH:8][C:16](=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14])([O-:3])=[O:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(CN)c(C)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3-Nitro-2,4-dimethyl-benzylamine (1.40 g, crude) is added to a mixture of 2,2-dimethyl-propionic acid chloride (0.682 mL, 5.5 mmol) and TEA (1.92 mL, 13.8 mmol) in THF (30 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 2 M aq. HCl-solution, 5% aq. NaHCO3 solution and water, dried with Na2SO4 filtered and concentrated.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][Si](C(C)C)(C(C)C)C(C)C)=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:27]O>>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]([F:22])[C:3]=1[C:4]([O:6][CH3:27])=[O:5]
Reactant: CC(C)[Si](Oc1ccc(F)c(C(=O)O)c1F)(C(C)C)C(C)C
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(F)ccc(O)c1F
Yield: 75 %

Procedure:
To a solution of 2,6-difluoro-3-triisopropylsilyloxy-benzoic acid (see example 2) (7 g, 21.1 mmol, 1.0 eq) in MeOH (100 mL) was added SOCl2 (10 mL) dropwise. The reaction mixture was heated at reflux for 3 h, then cooled and the solvent removed in vacuo. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a solid (3 g, 75%) which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[ClH:3].[CH3:4][C:5]([S:11][C:12]1[CH:13]=[CH:14][C:15]2[O:24][CH2:23][C:22]3[CH:21]=[CH:20][S:19][C:18]=3[C:17](=[C:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:16]=2[CH:32]=1)([CH3:10])[C:6]([O:8]C)=[O:7]>C(O)C>[ClH:3].[CH3:10][C:5]([S:11][C:12]1[CH:13]=[CH:14][C:15]2[O:24][CH2:23][C:22]3[CH:21]=[CH:20][S:19][C:18]=3[C:17](=[C:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:16]=2[CH:32]=1)([CH3:4])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)Sc1ccc2c(c1)C(=C1CCN(C)CC1)c1sccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(=C2c3cc(SC(C)(C)C(=O)O)ccc3OCc3ccsc32)CC1
Yield: 82.3 %

Procedure:
An aqueous solution (10 mL) of sodium hydroxide (0.82 g, 20.6 mol) was added to an ethanol (20 mL) solution of methyl 2-methyl-2-[4-(1-methylpiperidin-4-ylidene)-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-ylsulfanyl]propionate hydrochloride [Compound 189] (0.88 g, 1.8 mmol), and the mixture was refluxed while heating for 6 hours. The solvents were distilled off under a reduced pressure, the residue was then dissolved in water, the solution was neutralized with a diluted hydrochloric acid, and the precipitated crystals were separated by filtration and dried, to give 0.67 g (72%) of the captioned compound in the form of crystals.