Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]1[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([C:51](=[O:53])[CH3:52])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]([C:41]4[N:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[C:44]([C:51](=[O:53])[CH3:52])=[CH:43][N:42]=4)[CH:36]([CH:37]([CH3:38])[CH3:39])[C:24]3=[CH:23][C:22]=2[CH:21]=1
Reactant: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 15 h

Procedure:
The intermediate 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole was prepared following a procedure analogous to that described in Preparation 4. The mixture of compound 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (0.22 mmol), 1-(2-chloro-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (100 mg, 0.44 mmol) and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH2Cl2 (2 mL/1 mL) was stirred at 60° C. for 15 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1) to give racemic 1-(2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone. LC-MS m/z 510 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.97 (s, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 6.54 (s, 1H), 6.01-5.90 (m, 1H), 5.25-5.15 (m, 1H), 5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.15-4.04 (m, 1H), 4.00-3.93 (m, 1H), 3.26 (s, 3H), 2.55 (s, 3H), 2.41-2.32 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Li].IC1C=CC=CC=1C(F)(F)F>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([F:27])([F:26])[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: [Li]c1ccccc1C(F)(F)F
Agent: FC(F)(F)c1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C(F)(F)F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-trifluoromethylphenyllithium (˜3 equiv, freshly prepared from 1-iodo-2-trifluoromethylbenzene as in Example 2A), to give (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-trifluoromethyl-phenyl)-methanone. MS (M+H)+: 328.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([F:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1c(F)ccc(Br)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1c(F)ccc(Br)c1F)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (150 mg, 0.607 mmol) in toluene 15 mL was added 3-bromo-2,6-difluorobenzaldehyde 40 (81.4 mg, 0.607 mmol) and subsequently PTSA (230.9 mg, 1.214 mmol) was added, and stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 41. The crude 41 was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-bromo-2,6-difluorobenzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 41 was eluted at 32% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2[C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C#Cc2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of lithium hydroxide monohydrate (30 mg, 0.72 mmol) in water (0.9 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid methyl ester (121 mg, 0.36 mmol) in THF (0.9 mL) and methanol (0.2 mL). The reaction mixture was then stirred at room temperature for 18 h and was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (89 mg, 77%) as a light yellow solid after trituration with ethyl acetate. MS: m/e=321.1 [M−H]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][NH:8][C:9]([CH:11]1[CH2:15][C:14](=O)[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=O.O.[OH-].[Na+]>O1CCCC1>[CH3:7][NH:8][CH2:9][CH:11]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1
Reactant: CNC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCC1CCN(Cc2ccccc2)C1
Yield: 88.5 %

Procedure:
To a suspension of 37.40 g (1.00 mole) lithium aluminum hydride in 1000 ml tetrahydrofuran, is added a solution of 88.3 g (0.380 mole) of N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide in tetrafuran dropwise under nitrogen. The reaction was then refluxed overnight. The reaction flask was cooled in an ice bath and 37.4 ml of water, 37.4 ml of 15% sodium hydroxide and and 112.2 ml of water were added. The precipitated solids were filtered and washed with hot ethanol. The combined filtrates were concentrated, then dissolved in dichloromethane, filtered, dried over magnesium sulfate, and the solvent evaporated under reduced pressure to give 68.68 g of N-methyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as an oil. This material was used without further purification in the step.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:15]3)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:15]3)[CH2:7]1)(=[S:35])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)N1CCc2cc(N3C[C@H](CNC(C)=O)OC3=O)ccc2C1
Solvent: C1CCOC1
Product: COC(=O)N1CCc2cc(N3C[C@H](CNC(C)=S)OC3=O)ccc2C1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 134.2 %

Procedure:
A mixture of methyl 6-[(5S)-5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Example 1, 280 mg, 0.806 mmol) and Lawesson's reagent (179 mg, 0.443 mmol) in dry THF (8.1 mL) under N2 is heated up to 60° C. over 15 mins, stirred at this temperature for 5 mins, and then cooled to ambient temperature and concentrated under reduced pressure. The crude product mixture is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with MeOH/CH2Cl2 (2/98), and those fractions with an Rf=0.57 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the residue recrystallized from CH2Cl2/Et2O to give 216 mg (74%) of the title compound as an off-white solid, mp 149-150° C. (dec.); [α]25D=5° (c 0.99, DMSO).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7].[OH-].[Na+]>C(O)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:15])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:34])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:33])[N:25]([CH3:32])[C:26](=[O:31])[N:27]([CH3:30])[C:28]=2[CH3:29])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Temperature: 47.5 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester (2.2 mmol, 1.11 g) in ethanol (12 mL) was added aqueous 1.0 N sodium hydroxide (8.8 mL) at room temperature. The mixture was heated to 45-50° C. and the resulting clear solution was stirred for approximately 2 h. The ethanol was removed under reduced pressure and the residue was diluted with water (50 mL) and NaOH (5 mL, 1.0N) to dissolve the sodium salt. The aqueous solution was washed with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×75 mL). The combined organic extracts were washed with brine solution (100 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate afforded 970 mg (90% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine as a white solid: mp 225-227° C. FAB-HRMS m/e calcd for C23H21Cl2N3O5 (M+H) 490.0937, found 490.0940.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[CH2:14]([NH2:16])[CH3:15].[NH4+].[OH-]>O>[CH2:14]([NH:16][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:15]
Reactant: COC(=O)c1cccnc1Cl
Reactant: CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1ncccc1C(=O)OC

Procedure:
To 10 g. (0.06 mole) of methyl 2-chloronicotinate in 50 ml. of methanol was added 6.0 g. (0.13 mole) of ethylamine in 25 ml. of methanol and this was placed into an autoclave and heated on a steam bath for 4 hours. Then the reaction solution was stripped, water added, made very basic via NH4OH, extracted into CHCl3, washed with water, dried and then stripped to dryness to yield 2-ethylaminonicotinic acid, methyl ester. An HCl-salt was prepared by adding the crude residue to ethyl acetate and then adding ethereal-HCl. The product precipitated out of solution and was collected on a filter and rinsed with petroleum ether to give 7 g. of product with a m.p. of 140°-5° C.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>C1C=CC=CC=1>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:1]2[CH2:3][CH2:2]2)=[O:19])=[CH:21][CH:22]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: C1CN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)c1ccc(C(=O)N2CC2)cc1
Yield: 93.5 %

Procedure:
Aziridine (4.52 g) and 10.62 g of triethylamine were dissolved in 200 ml of benzene. p-Isopropylbenzoyl chloride (18.26 g) was dropped thereinto with stirring and keeping the inner temperature at 4° to 5° C. After the dropping, the mixture was stirred for 2 hours at the same temperature. After the reaction, the insoluble matters were removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (300 g of silica gel C-200; the eluting solvent was chloroform) to give 17.70 g of the product, yield: 94%.
Reaction SMILES: CS(O[CH2:6][C:7]([O:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-])=O)=[O:8])(=O)=O>[Fe].C(O)(=O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]2[NH:17][CH2:6][C:7](=[O:8])[O:9][C:10]=2[CH:15]=1
Reactant: CS(=O)(=O)OCC(=O)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1CNc2ccc(F)cc2O1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
50 g (0.17 mol) of 5-fluoro-2-nitro-phenyl methylsulphonyloxyacetate are added in portions at 60° C. to a suspension of 5 g (0.89 mol) of iron powder in 450 ml of 5 per cent strength aqueous acetic acid. During this process, the temperature of the suspension rises to 90° C. The mixture is stirred for another 30 minutes at 90° C. and, after cooling, the undissolved components are filtered off. The filtration residue is suspended repeatedly in warm methanol and the suspension is filtered. After concentration, the combined methanol filtrates give 21.3 g (75% of theory) of 7-fluoro-3H-1,4-benzoxazin-2(4H)-one having a melting point of 199° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 2-chloropyrimidine-4-carboxylic acid, 9.A (avialable from Anichem LLC, 1.00 g, 6.3 mmol), 1,3-dicyclohexylcarbodiimide (1.4 g, 6.9 mmol) and ethanol (0.32 g, 6.9 mmol) in DCM (10 ml) was stirred at room temperature overnight. The solid was filtrated off. DCM (80 ml) was added and washed with brine (30 ml) and dried over MgSO4. The solvent was evaporated. The crude product was purified by Cobi-Flash silica gel column to give 9.B. 0.74 g, yield, 63%. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=4.7 Hz), 7.95 (1H, d, J=4.7 Hz), 4.51 (2H, q, J=7.4 Hz), 1.45 (3H, t, J=7.0 Hz). MS ESI (pos.) m/e: 187.0 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1.CCOC([S-])=[S:20].[K+]>O.Cl>[SH:20][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 27.6 g of sodium nitrite in 200 cc of water is added dropwise at 0°, while stirring, to a suspension of 60.4 g of 4-aminophenyl-acetic acid in 200 cc of water and 80 cc of concentrated hydrochloric acid. After the addition is complete, the reaction mixture is stirred at the same temperature for a further 45 minutes. This cold diazonium salt solution is then added dropwise at room temperature to a mixture of 74 g of potassiumethyl xanthogenate, 120 cc of water and 300 cc of a 2 N soda solution, and heating is effected to 45° until gas evolution stops. The mixture is subsequently cooled to room temperature, the pH is adjusted to 1 with concentrated hydrochloric acid and the oiled xanthogenate ester is extracted with ether. After removing the solvent by distillation, the ester is taken up in 500 cc of ethanol, a solution of 90 g of potassium hydroxide in 500 cc of water is added and boiling at reflux is effected for 20 hours. The major portion of the ethanol is subsquently removed by the distillation at reduced pressure, the aqueous phase is cooled with ice, rendered acid with concentrated hydrochloric acid while stirring well, and extracted with ether. The ether extract is dried over sodium sulphate, the solvent is removed by distillation, whereby 4-mercapto-phenylacetic acid crystallizes. After recrystallization from ether/pentane, the acid has a M.P. of 101° to 103°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:29]1[CH:33]=[CH:32][C:31]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)=[CH:30]1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccoc4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 1.7 mmol), Furan-3-boronic acid (0.28 g, 2.5 mmol), Na2CO3 (2 M, 3.9 mL), and Pd(PPh3)2Cl2 (15 mg, 0.13 mmol) in toluene/ethanol (1:1, 12 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Furan-3-yl-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 67% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.IC1C=CC=CC=1.I[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([O:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(I)cc1
Reactant: Cc1cc(C)cc(O)c1
Solvent: Ic1ccccc1
Product: COc1ccc(Oc2cc(C)cc(C)c2)cc1

Procedure:
Example 3.1 was repeated, replacing the phenol with 244 mg of 3,5-dimethylphenol (2 mmoles) and the iodobenzene with 655 mg of 4-iodoanisole (2.8 mmoles), the latter being added at the same time as the 3,5-dimethylphenol, and taking the reaction time to 48 hours.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH3:11].C(OCC)C>O>[C:2]([O:6][N:7]=[C:10]([CH2:9][Cl:8])[CH3:11])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON
Reactant: CC(=O)CCl
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(CCl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.51 g of O-tert-butylhydroxylamine hydrochloride, 0.93 g of chloroacetone, and 10 ml of diethyl ether is stirred at room temperature for 3 hours, poured into water, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetone O-tert-butyloxime.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C[O-].[Na+].CO.[CH3:13][C@H:14]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:15]([C:20](OC)=[O:21])[C:16](OC)=[O:17].Cl>CO>[OH:21][C:20]1[C:15]([C@H:14]([CH3:13])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:16]([OH:17])[N:7]=[CH:5][N:6]=1
Reactant: N=CN
Reactant: COC(=O)C[C@@H](C)C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C[C@@H](C)c1c(O)ncnc1O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To the solution of formamidine acetate (1.05 eq) in methanol (5 vol) was added 29.2% NaOMe/methanol (3 eq) at 0° C. for 0.25 h and the mixture was stirred for 0.5 h. To this was added the mixture of (R)-trimethyl 2-methylpropane-1,1,3-tricarboxylate (1.1 kg, 20 L) and methanol (50% w/w) for 0.5 h. After warming to 20° C., the reaction mixture was stirred for 14 h. The reaction mixture was neutralized with 5% aq HCl at 0° C. When pH was about 7, the mixture was concentrated. To the mixture was added methanol (0.7 vol), the mixture was washed with MTBE (5 vol), acidified with HCl to pH about 2 at 2° C., and stirred for 1 h at 60° C. After cooling to 0° C., the mixture was filtered and the cake was washed with water (1 vol) and dried in vacuum at 50° C. to get the product as solid (0.8 kg, 66% yield, 96% purity).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.C(Cl)CCC>C(#N)C.O.Cl>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([C:13]2[C:8]([CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])=[C:9]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:10]=[CH:11][CH:12]=2)=[O:24])[N:32]=1
Reactant: NS(=O)(=O)c1ccccc1CN1CCCC1=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)c2cccc(S(N)(=O)=O)c2CN2CCCC2=O)n1
Yield: 46 %

Procedure:
To a suspension of 254 mg of the product of Example 2 in 10 mL of acetonitrile, containing 275 mg of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate, was added 0.15 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The resultant solution was stirred for 2 hours, diluted with 20 mL of water and acidified with 5 drops of concentrated hydrochloric acid. n-Butylchloride (10 mL) was added, stirred, and the white precipitate was filtered. The collected white solid was washed with a little water, suction dried and finally dried in vacuo @ 70° C. overnight to afford 200 mg of a white solid, m.p. 185°-187° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([C:11]2[NH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][NH:14][N:15]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
2-Chloro-4-(1H-pyrazol-5-yl)benzonitrile hydrochloride (8 g, 33.3 mmol) was charged to the reaction flask and methanol (74 ml), activated charcoal (0.36 g) and celite (0.46 g) were added. The reaction mixture was refluxed for 1 h, filtered, and the solid was washed with warm methanol. A half of the methanol was distilled out and water (40 ml) was added at 55° C. slowly. 50% NaOH solution (1.916 ml, 36.7 mmol) was added slowly, the mixture was stirred for 10 min and cooled to RT. MeOH was evaporated and residue cooled to RT. Water (49 ml) was added and the precipitate was filtered and washed with water and dried under vacuum overnight at 60° C. to obtain 6.21 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 6.99 (d, 1H), 7.86 (d, 1H), 7.96-8.01 (m, 2H), 8.24-8.16 (m, 1H).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])=[CH:21][CH:20]=1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: Nc1ccc(Cl)cc1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc2c(c1)CNCC2

Procedure:
Using the method described in Example 7, 2-acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 4-chloroaniline and the product was deacetylated to give 7-(4-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.