Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH3:21])=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2].C(O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][C:18]([O:20][CH2:21][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:17][C:16]3=[O:22])[C:7]=2[CH:23]=1)#[N:2]
Reactant: OCc1ccccc1
Reactant: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CC(OCc3ccccc3)=CC2=O)[C@@H]1O
Temperature: 80 °C

Procedure:
A mixture of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran (0.7 g), benzyl alcohol (0.92 ml) and methanesulfonic acid (0.01 g) was heated at 80° C. for 3 hours under reduced pressure (40 mbars). After cooling the residue was stirred with diethylether, and the insoluble product filtered off and washed twice with diethylether, to give 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-benzyloxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 248° C.
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[O:16]1CCC[CH2:17]1.C([Li])CCC.CN(C)C=O>CCOCC>[CH:1]1([C:5]2[C:13]([CH:17]=[O:16])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Temperature: -78 °C
Yield: 41 %

Procedure:
Into a three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 62.1, 5.00 g, 80%, 12.7 mmol) in a solvent mixture of tetrahydrofuran and Et2O (50 mL/50 mL). The solution was cooled to −78° C. then n-butyllithium (15 mL, 2.5 M in hexanes) was added drop-wise with stirring. N,N-Dimethylformamide (2.64 mL, 34.2 mmol) was added and the resulting mixture was stirred for 1 h at −78° C., then carefully quenched by slow addition of aqueous NH4Cl (sat., 50 mL). The pH was adjusted to 1-2 with aqueous hydrogen chloride (6 M), then diluted with ethyl acetate (100 mL) and washed with brine (4×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:1) as the eluent to furnish 1.62 g (41%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:27][CH3:28])[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-isobutyl-methyl-amine (1.54 g, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (4.18 g, 91%).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:31][N:30]([C:32](=[O:35])[CH:33]=[CH2:34])[CH2:29][CH2:28][C:26]=2[N:27]=1.[CH2:36]([OH:39])[C:37]#[CH:38]>>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:31][N:30]([C:32](=[O:35])[CH2:33][CH2:34][O:39][CH2:36][C:37]#[CH:38])[CH2:29][CH2:28][C:26]=2[N:27]=1
Reactant: C=CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCO
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCOCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 50 °C
Yield: 47.7 %

Procedure:
Add 1,8-diazabicyclo [5.4.0]undec-7-ene (0.035 mL; 0.15 equiv; 0.23 mmoles) to a solution of 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one (0.5 g; 1.0 equiv; 1.56 mmoles) and 2-propyn-1-ol (5.0 mL; 55 equiv; 85.86 mmoles). Stir the reaction at ambient temperature for 16 hours, then heat to 50° C. for 36 hours. Concentrate the solution to a brown oil, then purify the crude product by column chromatography (20 to 100% ethyl acetate in dichloromethane) to afford the desired 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-(prop-2-yn-1-yloxy)propan-1-one (0.28 g; 48%): MS (m/z): 377 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][C@H:7]1[CH2:19][OH:20])=[O:5])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14])[CH2:8][C@H:7]1[CH2:19][O:20][C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: Oc1ccc(F)cc1
Product: CCOC(=O)[C@@H]1CC(O[Si](C)(C)C(C)(C)C)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 5 using (1R,2R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxymethyl-cyclopentanecarboxylic acid ethyl ester (example 68 step 4) and 4-fluorophenol. Colorless oil (74%). MS (EI): 397.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(CC(=O)O)sc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of methyl 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetate (2 g) and 4N sodium hydroxide solution (3.7 ml) in tetrahydrofuran (20 ml) as stirred at ambient temperature for 1 hour. The mixture was diluted with water and washed with toluene. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was recrystallized from a mixture of ethanol and water to give pale orange crystals of 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]thiophene-2-acetic acid (1.6 g).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:9]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:35])=[N:10][O:11][C:12]=1[C:13]1[CH:14]=[N:15][N:16]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>O1CCOCC1.ClCCl>[Cl:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[C:9]1[C:8]([C:6]2[S:45][C:1]([CH3:2])=[N:4][N:5]=2)=[C:12]([C:13]2[CH:14]=[N:15][N:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:17]=2[C:18]([F:21])([F:20])[F:19])[O:11][N:10]=1
Reactant: CC(=O)NNC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2ccncc2)c1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nnc(-c2c(-c3c(F)cccc3Cl)noc2-c2cnn(-c3ccncc3)c2C(F)(F)F)s1

Procedure:
To a solution of N′-acetyl-3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-4-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carbohydrazide (0.029 mg, 0.01 mmol) in dioxane (1.5 mL) was added Lawesson's Reagent (23.1 mg, 0.01 mmol). The mixture was stirred at reflux for 30 min. The mixture was then diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Solvent: CC#N
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2
Yield: 27.3 %

Procedure:
A solution of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (100 mg, 0.182 mmol) and pyrrolidine (37.9 μl, 0.455 mmol) in acetonitrile (2 mL) was stirred in a sealed vial at 40° C. for 1 hour. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a white solid (29 mg). LCMS (Method F, ES-API): RT 2.48 min, m+H=585.3; 1H NMR (400 MHz, CDCl3): δ 8.63-8.61 (1H, m), 8.43 (1H, d, J=2.4 Hz), 7.89-7.87 (1H, m), 7.80 (1H, dt, J=7.6, 1.8 Hz), 7.58 (1H, dd, J=9.0, 2.4 Hz), 7.45-7.41 (3H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.47 (1H, d, J=2.1 Hz), 6.22 (1H, d, J=9.0 Hz), 5.46 (1H, dd, J=12.2, 2.1 Hz), 4.27 (1H, d, J=16.9 Hz), 3.83-3.79 (1H, m), 3.52-3.45 (4H, m), 2.90-2.76 (2H, m), 2.68 (1H, d, J=12.3 Hz), 2.51-2.45 (2H, m), 2.06-2.04 (4H, m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:52]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[N:45]=[C:44]([NH2:53])[C:43]=2[N:42]=[C:41]1[CH2:54][CH2:55][CH2:56][CH3:57]>CN1CCCC1=O>[NH2:53][C:44]1[C:43]2[N:42]=[C:41]([CH2:54][CH2:55][CH2:56][CH3:57])[N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])[C:52]=2[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[N:45]=1
Reactant: O=C(O)c1cc2ccccc2cn1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1cc2ccccc2cn1
Reaction time: 0.29 h
Yield: 75.4 %

Procedure:
Isoquinoline-3-carboxylic acid (1.05 g, 6.05 mmol) was stirred in 1-methyl-2-pyrrolidinone (50 mL). 1-Hydroxybenzotriazole (885 mg, 6.55 mmol) was added in a single portion. This solution was stirred for 15-20 minutes and then cooled in an ice bath. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.26 g, 6.55 mmol) was added in small portions over a period of 10 minutes. The solution was stirred for 1 hour and then added dropwise to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine-(1.50 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (100 mL). After 3 hours the reaction mixture was poured into distilled water (800 mL). A solid precipitated. This material was stirred for 5 hours, isolated by filtration and then air dried over the weekend. The solid was taken up in chloroform (100 mL) and then purified by column chromatography (silica gel eluting sequentially with chloroform (1 L), 1% methanol in chloroform (1 L) and 5% methanol in chloroform (1 L)). The purified material was slurried with hot acetonitrile, cooled, isolated by filtration and then dried in a vacuum oven to provide 1.72 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]isoquinoline-3-carboxamide as a solid, m.p. 203.8-205.3° C. Analysis: Calculated for C27H28N6O: % C, 71.66; % H, 6.24; % N, 18.57; Found: % C, 71.63; % H, 6.17; % N, 18.57.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:16]=[C:15]([O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:14]=[C:13]([O:18][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:12]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)CN(CC(=O)OC)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)OC)CC(=O)OC)c1
Reaction time: 48 h
Yield: 52.8 %

Procedure:
A mixture of 0.50 g (1.86 mmol) of N-[(3,5-Dihydroxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.81 ml (3.9 mmol) of 1-bromodecane and 0.77 g (5.57 mmol) of potassium carbonate in 15 ml of acetone was stirred at reflux for 24 hours. An additional 0.8 ml of 1-bromodecane was added and reflux was continued for 48 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated at reduced pressure to an oil which was purified by HPLC using 15% ethyl acetate-hexane to give 0.54 g (52% yield) of N-(2-methoxy-2-oxoethyl)-N-[3,5-bis-(decyloxy)phenyl]glycine methyl ester as an oil. The nmr and mass spectra of this product were identical to those obtained using the procedure of Example 5.
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:18])[C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Cl)c1F

Procedure:
To 2,6-difluoro-3-(propane-1-sulfonylamino)-benzoic acid (45, 1.50 g, 5.4 mmol) was added toluene (7.0 mL) and thionyl chloride (15.0 mL, 0.21 mmol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to give crude compound that was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[I:11]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([I:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1ccc(F)c(Cl)c1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc(Cl)c(F)cc1I
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a solution of 3-chloro-4-fluoroanisole (4.69 g, Lancaster) in chloroform (250 mL) was added silver trifluoroacetate (23.2 g, Aldrich) followed by iodine (15.8 g, Aldrich) in several portions. The reaction mixture was stirred for 2 hours and filtered through Celite. The filtrate was washed with water, brine, dried and concentrated. The crude product was purified by crystallization from ether/petroleum ether to give 5-chloro-4-fluoro-2-iodoanisole (5.0 g). MS (M+H)+, 285.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=2)=[CH:2]1.[OH-].[Na+].CO>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(=O)Nc1ccc(-c2ccsc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccsc2)cc1
Yield: 115.5 %

Procedure:
A mixture of N-(4-thiophen-3-yl-phenyl)-acetamide (90 mg, 0.41 mmol), NaOH (133 mg, 3.3 mmol), MeOH (2 mL) and water (7 mL) was heated to reflux for 12 hr. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine solution and dried over sodium sulphate. The organic layer collected was concentrated under reduced pressure to afford 83 mg (crude) of 4-thiophen-3-yl-phenylamine.
Reaction SMILES: Br[C:2]1(Br)[CH2:10][C:9]([CH3:12])([CH3:11])[C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:11][C:9]1([CH3:12])[C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:3]2[N:24]=[C:22]([NH:21][C:16]3[N:17]=[CH:18][CH:19]=[CH:20][N:15]=3)[S:23][C:2]=2[CH2:10]1
Reactant: NC(=S)Nc1ncccn1
Reactant: CC1(C)CC(Br)(Br)C(=O)c2cn[nH]c21
Solvent: CCO
Product: CC1(C)Cc2sc(Nc3ncccn3)nc2-c2cn[nH]c21
Reaction time: 0.67 h
Yield: 1477832.5 %

Procedure:
According to Scheme 2 Step 4: A solution of 5,5-dibromo-7,7-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (6.09 mmol, 1.96 g) and of 1-(pyrimidin-2-yl)thiourea (6.09 mmol, 939 mg) in ethanol (18 mL) was microwaved at 150° C. for 90 minutes and then at 140° C. for 40 minutes. After filtration, the reaction mixture was concentrated to dryness. The crude residue was partitioned between DCM and a saturated solution of Na2CO3. The aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by flash chromatography over silica gel using DCM/MeOH (98:2 to 90:10) as eluent to yield 5,5-dimethyl-N-(pyrimidin-2-yl)-5,6-dihydro-4H-thiazolo[4,5-e]indazol-2-amine (90 mol, 27 mg) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH2:25].S1C=CN=C1C1SC2C(=NC=CC=2OC2C=CC(N[C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)=[S:49])=CC=2F)C=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:19]4[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=4)[S:18][C:11]=23)[CH:6]=[CH:5][C:4]=1[NH:25][C:48]([NH:50][C:51](=[O:59])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[S:49]
Reactant: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1N
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: COc1cc(Oc2ccnc3cc(-c4nccn4C)sc23)ccc1NC(=S)NC(=O)Cc1ccccc1
Yield: 48 %

Procedure:
Starting from compound 216 and following the procedure described above for the synthesis of compound 13a (scheme 2, step 5, example 12), title compound 217 was obtained in 48% yield. 1H NMR (400 MHz,DMSO-d6) δ ppm. 12.07 (1H, s), 11.59 (1H, s), 8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d, J=8.80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H, m), 6.66 (1H, d, J=5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][S:9](O)(=[O:11])=[O:10].O=S(=O)=O>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9]([OH:11])(=[O:10])=[O:8])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccccn1
Agent: O=S(=O)=O
Product: Nc1ccc(S(=O)(=O)O)cn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
2-Aminopyridine (80 g, 0.85 mol) was added portionwise over 30 minutes to stirred oleum (320 g) and the resulting solution heated at 140° C. for 4 hours, then allowed to cool. The reaction mixture was poured onto stirred ice (200 g) and this mixture stirred at ice-salt bath temperature for a further 2 hours. The resulting suspension was filtered, then the collected solid washed successively with ice-water (200 ml) and cold industrial methylated spirit (IMS) (200 ml) and, finally, dried under suction to provide the title compound (111.3 g, 75%) as a solid. LRMS: m/z 175 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([NH:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([N:19]([CH2:20][C:21]#[N:22])[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:24][CH:23]=1)=[O:8])=[O:5]
Reactant: N#CCNc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: c1ccccc1
Product: N#CCN(C(=O)NC(=O)c1c(Cl)cccc1Cl)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 80 %

Procedure:
16.0 g of 2,6-dichlorobenzoylisocyanate are added in small portions to a solution of 11.66 g of p-chloroanilino-acetonitrile in 100 ml of dry benzene with moderate cooling. After some time a substance crystallizes out, which after about 12 hours is drawn off and washed with benzene. After drying the weight is 25.25 g, i.e. 93.7% the melting point being 185° C. with spontaneous decomposition on the Kofler heating bench. Thin-layer chromatography (solvent either ethylacetate or chloroform) shows that the substance is pure, however, if desired, it may be recrystallized from 250 ml of benzene with a yield of 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCCCCC>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (66.2 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.5 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (49.5 mg, 55%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-Toluidine (6.430 g, 60 mmol) was dissolved in pyridine (200 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.784 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-methylphenyl)benzenesulfonamide (9.4754 g, 89%), was obtained as a colorless solid, in 98% purity by HPLC (MaxPlot detection between 230 and 400 nm).