Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].Cl.C(NCC)C>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 79.2 %

Procedure:
To a solution of 132.6 g of o-nitrobenzenesulfonyl chloride in 700 ml of tetrahydrofuran was added 88.5 g of diethylamine at 5°-15°. The reaction mixture was stirred at room temperature for 1 hour before the precipitated diethylamine hydrochloride was removed by filtration. The filtrate was evaporated to dryness in-vacuo and the residue dissolved in 1-chlorobutane. The 1-chlorobutane solution was washed with water, dried over magnesium sulfate and evaporated in-vacuo to give 122.4 g of o-nitro-N,N-diethylbenzenesulfonamide as a dark oil.
Reaction SMILES: [CH3:1][C@@:2]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3]1.P(OCC)(OCC)[O:24]CC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[OH:24][CH:6]1[C:5](=[O:7])[N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:3][C@:2]1([CH3:1])[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17]
Reactant: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)CC1=O
Reactant: CCOP(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@](C)(C(=O)OC(C)(C)C)C(O)C1=O
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of tert-butyl (3R)-3-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (9.90 g, 32.6 mmol) and tri ethyl phosphite (6.71 mL, 39.1 mmol) in anhydrous tetrahydrofuran (165 mL), lithium bistrimethylsilyl amide (45.7 mL, 45.7 mmol, 1.0M solution in tetrahydrofuran) was added at −5° C., and the mixture was stirred at the same temperature for 30 minutes. After bubbling oxygen gas into the reaction mixture for 30 minutes, saturated aqueous solution of ammonium chloride (150 mL) was added in an ice bath, and the mixture was concentrated under reduced pressure. Water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate, 1:1→1:4) to obtain 7.73 g (74%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:17][CH3:18]>CC(C)=O.C(OCC)(=O)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[O:8][CH2:17][CH3:18]
Reactant: Nc1ncnc(Cl)c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOc1c(N)ncnc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (1000.0 mg; 6.8 mmol; 1.0 eq.), cesium carbonate (2686.3 mg; 8.24 mmol; 1.2 eq.), and iodoethane (1285.9 mg; 8.24 mmol; 1.2 eq.) in acetone (10 ml) was stirred at 50° C. overnight. The reaction solution was diluted with ethyl acetate (50 ml), washed with water, then brine, dried and concentrated. The residue was treated with ether, stirred for 30 min, filtered, collected white off solid as title compound (1165 mg in yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.018 ml propionyl chloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 79 mg of a light brown solid (96%). MS (ISP) 507.3 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23][NH2:24])=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>C(O)(=O)C>[C:13]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(C(=O)NN)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-tert-butylbenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 168 mg of the title compound (75%) as a yellow solid in 99.8% purity by HPLC (Rt: 6.65, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>ClCCl>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22](=[O:23])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reaction time: 3 h
Yield: 36 %

Procedure:
To a stirred of mixture of 56 ml of 1,3-difluorobenzene, 130 g of aluminium chloride and 147 ml of dichloromethane, a solution of 95 g of 1-acetyl-4-piperidinecarbonyl chloride in 50 ml of dichloromethane was added dropwise while cooling. Upon completion, stirring was continued for 3 hours at room temperature. The reaction mixture was poured out into a mixture of crushed ice and hydrochloric acid. The product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, yielding 48 g (36%) of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine as a residue (interm. 1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:32][NH:33][CH2:34][CH3:35]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:24]2[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[CH2:26][CH2:25]2)[C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][O:20]2)=[O:18])[CH2:13][C@H:9]1[C:10]([N:33]([CH2:34][CH3:35])[CH3:32])=[O:12])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CCNC
Reactant: CC1(C)CCC(N(C(=O)[C@@H]2CCCO2)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Product: CCN(C)C(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1, using (4S)-1-BOC-4-{(4,4-dimethylcyclohexyl)[(2S)-tetrahydrofuran-2-ylcarbonyl]amino}-L-proline (0.96 g, 2.2 mmol) prepared in Step B and commercially available N-methylethylamine (0.92 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].COC1C=CC(/C=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:38][C:37]1[S:39]/[C:33](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:16]#[N:17])=[C:4]3[O:3][CH2:1][CH3:2])/[C:34](=[O:35])[N:36]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12
Temperature: 110 °C
Yield: 46.2 %

Procedure:
To the suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e) (45 mg, 0.2 mmol) and pseudothiohydantoin (35 mg, 0.3 mmol) in acetic acid (1 mL) was added sodium acetate (66 mg, 0.8 mol). The mixture was heated to 110° C. for 4 h. After cooling to room temperature, the ice water was added. The solid was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile (30 mg, 47%) as a light yellow solid: LC-MS m/e 445 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH:32]([NH2:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH:32]([NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:33]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCC(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 73.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (86 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 1-methoxy-2-propylamine (24 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 480.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.18 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 4.30-4.15 (m, 1H), 3.62 (bs, 3H), 3.42 (dd, 1H), 3.29 (dd, 1H), 3.27 (s, 3H), 1.14 (d, 3H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH2:7][CH2:6][NH:5]1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].[Cl-].[Na+]>O1CCCC1>[CH3:30][O:29][C:25]([CH2:26][CH2:27][N:5]1[CH2:6][CH2:7][C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:9][C:4]1=[O:3])=[O:28]
Reactant: C=CC(=O)OC
Reactant: O=C1C=C(c2c(-c3ccccc3)nn3ccccc23)CCN1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCN1CCC(c2c(-c3ccccc3)nn3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
Sodium hydride (60%, 43.6 mg) was added to a mixture of 3-(2-oxo-1,2,5,6-tetrahydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (210 mg), methyl acrylate (93.8 mg) and tetrahydrofuran (2.1 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. A saturated solution of sodium chloride (20 ml) was added to the reaction mixture and extracted with ethyl acetate (20 ml×2). The combined extract was washed with a saturated solution of sodium chloride (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethyl acetate (10:1) to give 3-[1-[2-methoxycarbonylethyl)-2-oxo-1,2,5,6-tetrahydropyridin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (210.7 mg) as an oil.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>CO.[OH-].[Na+].O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]([CH3:23])[N:13]([C:24](=[O:28])[NH:25][CH2:26][CH3:27])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CCNC(=O)N1N=C(c2ccc(NC(C)=O)cc2)c2cc(SC)ccc2C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNC(=O)N1N=C(c2ccc(N)cc2)c2cc(SC)ccc2C1C
Yield: 87 %

Procedure:
The solution of acetyl amide 9 in methanol and NaOH (2 N) was refluxing until there is no more starting material left monitored by TLC. The solution was diluted with water, and extracted with DCM three times. Removal of the solvent afforded the crude product, which was purified by using a silica gel column, gave the desired products 12 (Yield: 87%). 1HNMR (CDCl3): 7.45 (d, J=8.6 Hz, 2H), 7.35−7.25 (m, 4H), 6.78 (d, J=8.6 Hz, 2H), 6.53 (br, 1H), 5.60 (q, J=13.2 Hz, 1H), 3.42 (m, 2H), 2.40 (s, 3H), 1.22 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12]([NH2:15])([CH3:14])[CH3:13]>CO>[CH:12]([NH:15][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])([CH3:14])[CH3:13]
Reactant: NS(=O)(=O)c1cnccc1Cl
Reactant: CC(C)N
Solvent: CO
Product: CC(C)Nc1ccncc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 4-chloropyridine-3-sulfonamide are dissolved in 50 cm3 of methanol and 50 cm3 of isopropylamine. The solution is introduced into a sealed tube and brought to 120° C. for 18 hours. After cooling, the reaction mixture is concentrated to dryness under vacuum (rotary evaporator) and the residue is taken up in 200 cm3 of water. The precipitate corresponding to the title compound is collected on a filter and washed with water. The precipitate is redissolved in 100 cm3 of dilute NaOH. The solution is decolored with charcoal, filtered and then acidified to a pH of 6.5-7. The crystalline precipitate obtained is collected on a filter, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][NH2:25])=[CH:21][CH:20]=1>O1CCCC1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([CH2:23][CH2:24][NH:25][S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccc(F)cc1)c1ccc(Br)s1
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonyl chloride (600 mg) in tetrahydrofuran (5 mL) was added dropwise triethylamine (0.64 mL) and 4-fluorophenethylamine (0.36 mL) on an ice bath. After stirring for 15 minutes on an ice bath, the solution was further stirred at room temperature for 2 hours. After dilution with ethyl acetate and washing with 5N hydrochloric acid, water, an aqueous solution of saturated sodium bicarbonate and saturated sodium chloride water, the solution was dried with anhydrous sodium sulfate. Silica gel filtration was carried out, and the solvent was removed by evaporation to provide the title compound (860 mg) as a colorless oily matter.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[I-].[K+].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCCC3)CC2)nc1N
Temperature: 90 °C
Yield: 45.2 %

Procedure:
A suspension of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (25 mg, 0.051 mmol, Example 272), potassium iodide (30 mg, 0.18 mmol), and pyrollidine (400 mg, 5.6 mmol) in dioxane (8 mL) was heated at 90° C. under nitrogen for 14 hours. The resulting solution was concentrated to ˜1 mL and triturated with water. Solids were filtered and dissolved in methylene chloride. After washing with water, the organic layer was separated and dried (Na2SO4). The product was purified by trituration with tetrahydrofuran/ethyl ether and filtered to give [4-amino-2-[1-(3-pyrrolidin-1-yl-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid (12 mg, 40% yield). HRMS, observed: 521.2343; Calcd for (M+H)+: 521.2341
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13]Br>CCOCC>[Br:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccsc1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccsc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
3-Acetylthiophene (6.3 g, 50 mmol) was dissolved in anhydrous ether (100 ml) and aluminium chloride (catalytic amount) added. Bromine (2.55 ml, 50 mmol) was added dropwise and then stirred for 10 min. The ether was removed under reduced pressure and the residue washed with water. The crude product was recrystallised from petroleum-ether (60°-80° C.) to yield 3-bromoacetylthiophene m.p. 54°-56° C. (8.76 g, 85%), δH (CDCl3) 8.15(1H, dd, H2), 7.55(1H, dd, H4'), 7.35(1H, dd, H5').
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1.CC(C)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (3.05 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00 M, 2.54 mL) at 0 degrees celsius and the resulting solution was stirred at rt for 1 hour. The mixture was flustered through celite and the filtrate was concentrated. The resulting residue was dissolved in AcOEt, washed with water and brine successively, dried with MgSO4, and concentrated in-vacuo. The crude product was purified by Combiflash eluting with 40% AcOEt in hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.O>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-methylthiophene-2-carbaldehyde (5.7 g) in chloroform (40 mL) was added dropwise bromine (2.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was and stirred at 0° C. for 30 min, and then at room temperature for 1 hr, and then under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (8.1 g, 88%) as a brown solid.
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.CN(C=O)C.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Cu]I.CO>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:5]=[N:6][NH:7][CH:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(-c3c[nH]nn3)cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Trimethylsilyl azide (415 mg, 3.6 mmol) was added to a DMF (4.3 mL) and MeOH (0.48 mL) solution containing CuI (22.9 mg, 0.12 mmol) and 1-(benzyloxy)-4-ethynylbenzene (500 mg, 2.4 mmol) under Ar in a pressure tube (caution: build-up of pressure possible; use a safety shield). The reaction mixture was stirred at 100° C. for 12 h. The mixture was cooled to room temperature and filtered through a short silica gel pad and concentrated. The residue was purified by recrystallization from DCM.
Reaction SMILES: [CH3:1][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:32])=O>>[CH3:1][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([CH2:18][CH2:19][NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:3][CH2:4][C:5]([Cl:32])=[O:6]
Reactant: CN(CCC(=O)O)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Reactant: O=S(Cl)Cl
Product: CN(CCC(=O)Cl)c1ccc2cccc(CCNC(=O)Cc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product obtained in Step B (3 mmol), dissolved in thionyl chloride, is stirred at 60° C. under a stream of nitrogen for one hour. The thionyl chloride is evaporated off under reduced pressure and the residue is dried using a vane pump to yield the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(Cl)cc2)cc1
Temperature: 77.5 °C
Yield: 61.5 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (8 g, 26 mmol) and sodium bicarbonate (4.36 g, 52 mmol) in isopropanol (240 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating the reaction mixture at 75-80° C. for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product (16.2 g) was purified by chromatography (silica gel, hexane/ethyl acetate, 55/45) to give pure 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (6.7 g, 62%) as a white solid: Anal. Calc'd. for C17H14N2SO3ClF3: C, 48.75, H, 3.37, N, 6.69. Found: C, 48.56, H, 3.22, N, 6.51.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[N:13](C(OC(C)(C)C)=O)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]1[CH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>C(Cl)Cl>[S:28]1[CH2:27][CH2:26][CH:25]([N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[NH:13][C:9]2=[O:8])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(C2CCSCC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n1C1CCSCC1
Reaction time: 2 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl 2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylate from Step A (210 mg, 0.628 mmol) in CH2Cl2 (3 mL). After 2 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=235 (M+1).