Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](Cl)=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[N+:17](=[CH2:19])=[N-:18].CC(O)=O>C1COCC1>[N+:17](=[CH:19][C:14]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:15])=[N-:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc2ccccc12
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [N-]=[N+]=CC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a solution of 3-nitro-napthalene-1-carbonyl chloride (8.4 g, 35.7 mmol) in anhydrous THF (70 mL) was added an ethereal solution of diazomethane (250 mL) dropwise at 0° C. The reaction mixture was stirred for 5 h, and then warmed to RT overnight. Excess diazomethane was decomposed by the dropwise addition of AcOH (50 mL). The mixture was extracted with Et2O (3×150 ml), washed with brine and saturated NaHCO3 aqueous solution, dried and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography to yield 2-diazo-1-(3-nitronaphthalen-1-yl)ethanone (7.0 g, 81% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.47 (d, J=7.2 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.35 (s, 1H), 7.84 (t, J=7.2 Hz, 2H), 7.76 (t, J=7.8 Hz, 2H), 6.84 (s, 1H); MS (ESI) m/z: 242 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[N:18]=O.[CH:20](O)=[O:21]>[Zn]>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[NH:18][CH:20]=[O:21]
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Reactant: O=CO
Agent: [Zn]
Product: Nc1c(NC=O)c(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Temperature: 55 °C

Procedure:
150.0 g of 6-amino-1-(4-chlorobenzyl)-5-nitroso-uracil were dissolved in 1.2 liters of formic acid at 70° C. and treated over 1.5 hours in portions with 76.84 g of zinc powder keeping the temperature between 75-80° C. After cooling to 55° C. the solid was filtered of, the residue resuspended in 800 ml of formic acid and the solid again filtered off. The filtrates were evaporated to a solid which was suspended in 350 ml of water. The solid was collected, washed and dried to give the title compound (149.1 g) as a white solid, mp 274-8° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1(=[O:23])[N:7]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:6](=[O:18])[C:5]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:4]12>C(O)C>[OH:23][CH2:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)=[O:18]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCOc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Sodium borohydride [3.78 g (100 mmol)] was added to a solution of 2.82 g (10.0 mmol) of 4-(3-phthalimidopropyloxy)pyridine in 150 ml of ethanol. The mixture was stirred at room temperature for 3 hours. After the solvent was distilled off, brine was added to the residue. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off and then the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.488 g of the desired compound (yield: 52.0%, colorless crystals).
Reaction SMILES: [SH:1][CH2:2][CH:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:17](=O)([O-])[O-:18].[K+].[K+].O.C1N=CN(C(N2C=NC=C2)=O)C=1>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]2[C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][S:1][C:17]2=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(CNC(CS)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)O)cc1
Temperature: 40 °C

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 3-mercapto-2-(4-methoxybenzylamino)-propionic acid (400.0 g, 1.66 mol), potassium carbonate (480.0 g, 3.47 mol) and 2.80 L of water. The mixture was heated at 40° C. with stirring until it became homogeneous and was then cooled to 20-25° C. A solution of N,N-carbonyldiimidazole (400.0 g, 222.47 mol) in 2.8 L of acetonitrile was added while maintaining an internal reaction temperature of less than 30° C. The reaction was monitored by HPLC and was complete upon the disappearance of starting material. The acetonitrile was removed by distillation at 40° C. and 80-100 torr. Iso-propyl acetate (200 mL) was added and the pH of the mixture was adjusted to 2 with 150 mL of 3M H2SO4. The biphasic mixture was filtered, separated and the organic layer azeotropically dried by distillation at atmospheric pressure. The final measured water content was less than 0.5%. The resulting solution was further diluted with 1.8 L of iso-propyl acetate and used in the next example. 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.3 Hz, 2H), 6.88 (d, 8.3 Hz, 2H), 4.52 (AB, JAB=15.5 Hz, ΔvAB=238.4 Hz, 2H), 4.31-4.24 (m, 1H), 3.71 (s, 3H), 3.67-3.59 (m, 1H), 3.36-3.28 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1>>[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[CH:8][C:9]=3[F:16])=[O:13])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)n1
Yield: 36 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (291 mg) described in Preparation Example 23 and 1-(2,6-dimethylpyridin-3-yl)piperazine (215 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (175 mg) was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:24]2([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]2)[O:23][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:22])[CH2:11]2.[Br:31]Br>O1CCCC1>[Br:31][C@@H:13]1[CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][C@@H:4]3[O:23][C@@:24]4([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11][C:12]1=[O:22]
Reactant: BrBr
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@H](Br)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of (5α,25R)-spirostan-3-one (1.00 g, 2.41 mmol) and tetrahydrofuran (10 mL) was cooled to -78° C. under nitrogen atmosphere. Bromine was added (0.39 g, 2.41 mmol) and the reaction mixture was gradually warmed to room temperature. After three hours, the reaction was quenched by the addition of saturated sodium bisulfite solution. The mixture was diluted with ethyl acetate, washed with saturated sodium bisulfite solution (1x), saturated sodium bicarbonate (1x), brine (1x), dried (sodium surfate), filtered, and concentrated in vacuo. Upon addition of ether, a precipitate formed which was filtered and washed with hexanes to give 1.20 g, (85%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:44][CH2:43]2)[CH:39]=[CH:38][C:37]=1[NH2:52].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:52][C:37]3[CH:38]=[CH:39][C:40]([CH:42]4[CH2:43][CH2:44][N:45]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH2:46][CH2:47]4)=[CH:41][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(C2CCN(CC(C)C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 55.3 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]aniline (Example 160, step C) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (72 mg, 0.105 mmol, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.23 Hz, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.13 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.69 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.57-7.65 (m, 2H), 7.43-7.49 (m, 1H), 7.35-7.43 (m, 1H), 7.16-7.22 (m, 2H), 6.99 (t, J=6.87 Hz, 1H), 6.95 (d, J=1.28 Hz, 1H), 6.78 (dd, J=8.24, 1.28 Hz, 1H), 6.48-6.54 (m, 1H), 3.82 (s, 3H), 2.90 (d, J=10.62 Hz, 2H), 2.40-2.46 (m, 1H), 1.97-2.05 (m, 2H), 1.91 (t, J=10.62 Hz, 2H), 1.65-1.76 (m, 5H), 0.84 (d, J=6.59 Hz, 6H). MS (ESI): 688 [M+H]+.
Reaction SMILES: CN1CCCC1=O.[F:8][C:9]1[C:10]([NH:17][CH3:18])=[N:11][C:12](F)=[C:13]([F:15])[CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[CH2:19]([NH:26][C:12]1[C:13]([F:15])=[CH:14][C:9]([F:8])=[C:10]([NH:17][CH3:18])[N:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CNc1nc(F)c(F)cc1F
Solvent: ClC(Cl)Cl
Solvent: CN1CCCC1=O
Product: CNc1nc(NCc2ccccc2)c(F)cc1F
Temperature: 140 °C
Reaction time: 19 h

Procedure:
To 20 ml of N-methylpyrrolidone were added all amount of the above-described 3,5,6-trifluoro-2-(methylamino)-pyridine together with 10 g of benzylamine, and the mixture was stirred at 140° C. for 19 hours and allowed to cool. To the solution was added 50 ml of chloroform and the mixture was washed six times with 200 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound as a crude oil.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].[CH3:7][O:8][CH2:9]OC>C(Cl)Cl>[Br:1][CH2:2][CH:3]([O:6][CH2:7][O:8][CH3:9])[CH2:4][Br:5]
Reactant: OC(CBr)CBr
Reactant: COCOC
Solvent: ClCCl
Product: COCOC(CBr)CBr

Procedure:
1,3-Dibromo-2-propanol, dimethoxymethane, and boron trifluoride diethyl ether complex were reacted in methylene chloride at room temperature to obtain 1,3-dibromo-2-(methoxymethoxy)propane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][N:17](C=O)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[ClH:22]>CO>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=CN1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccc(-c2ccc(N3CCNCC3)nc2)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
4-(5-(4-Fluoro-phenyl)-pyridine-2-yl)-piperazine-1-carbaldehyde (98 mg, 0.34 mmol) was dissolved in MeOH (5 ml) and conc. HCl (12M, 5 ml) was added. The mixture was stirred at room temperature over night. The solvents were removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH/Toulene affording 102 mg (100%) of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]12[CH2:13][CH2:12][CH:5]([C:6](=[N:10][OH:11])[C:7]1=[N:8][NH2:9])[CH:4]([CH3:14])[O:3]2.CO[C:17](OC)(OC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:17]2[N:9]=[N:8][C:7]3[C:2]4([CH3:1])[CH2:13][CH2:12][CH:5]([CH:4]([CH3:14])[O:3]4)[C:6]=3[N+:10]=2[O-:11])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(OC)(OC)c1ccccc1
Reactant: CC1OC2(C)CCC1C(=NO)C2=NN
Product: CC1OC2(C)CCC1c1c2nnc(-c2ccccc2)[n+]1[O-]

Procedure:
A solution of 1.97 g. (0.01 mole) 1,3-dimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate gives 3-phenyl-5,8-dihydro-6,8-dimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][O:5][CH2:4]1.[N:9]1[O:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[CH:15]=[CH:14][C:13]=12>>[O:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][C:18]([C:16]2[CH:15]=[CH:14][C:13]3=[N:9][O:10][N:11]=[C:12]3[CH:17]=2)=[O:19])[CH2:4]1
Reactant: O=C(Cl)c1ccc2nonc2c1
Reactant: NC1CCCOC1
Agent: Cl
Product: O=C(NC1CCCOC1)c1ccc2nonc2c1

Procedure:
N-(Tetrahydro-2H-pyran-3-yl)-[2,1,3]-benzoxadiazole-5-carboxamide was prepared from 3-aminotetrahydropyran hydrochloride and [2,1,3]-benzoxadiazole-5-carbonylchloride using the procedure described for Example 7. Mp=204-205° C., 1H NMR (300 MHz, CDCl3) δ 8.24-8.10 (m, 1H), 7.93 (dd, 1H, J=9.0 and 0.9 Hz); 7.84 (dd, 1H, J=9.0 and 1.2 Hz); 6.70-6.60 (m, NH, 1H); 4.24-4.22 (m, 1H), 3.86-3.60 (m, 4H) and 1.97-1.61 ppm (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:4].[O:14]=[C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[NH:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:22][CH2:21][CH:20]([N:19]2[C:18]3[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=3[NH:16][C:15]2=[O:14])[CH2:25][CH2:24]1
Reactant: O=C(CBr)Nc1ccc(F)cc1F
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)Nc1ccc(F)cc1F

Procedure:
4 g (16 mmol) of the bromoacetanilide from Example I and 4.2 g (19 mmol) of 4-(2-oxo-1-benzimidazolinyl)piperidine in 50 ml of dimethylformamide are stirred at RT for 18 h with 2.6 g (19 mmol) of potassium carbonate. The solid is then filtered off with suction, the filtrate is partitioned between ethyl acetate and water, and the aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried (MgSO4) and concentrated. The residue obtained is triturated with ether, and the solid is filtered off and then recrystallized from methanol.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[C:7]([CH3:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[C:4]2[NH:13][C:14](=[O:24])[N:15]([C:16]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=3[F:23])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C1COCC1>[CH:35]1([S:38]([N:13]2[C:4]3=[CH:5][C:6]4[C:10]([C:2]([F:1])=[C:3]3[N:15]([C:16]3[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=3[F:23])[C:14]2=[O:24])=[N:9][N:8]([CH3:11])[C:7]=4[CH3:12])(=[O:40])=[O:39])[CH2:37][CH2:36]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c2cc3[nH]c(=O)n(-c4ccc(I)cc4F)c3c(F)c2nn1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c2cc3c(c(F)c2nn1C)n(-c1ccc(I)cc1F)c(=O)n3S(=O)(=O)C1CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.3 %

Procedure:
To a solution of 8-fluoro-7-(2-fluoro-4-iodophenyl)-2,3-dimethyl-2,7-dihydro-5H-imidazo[4,5-f]indazol-6-one (34 mg, 0.077 mmol) in THF (5 ml) at −78° C. was added LiHMDS (0.12 ml, 1 M in THF, 0.12 mmol). The reaction mixture was stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (22 mg, 0.15 mmol) was added to the mixture. The reaction was slowly warmed to room temperature and stirred at the temperature for 16 h. The reaction was quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution was washed with brine (20 ml), dried over MgSO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yields 24 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[C:25]=1[CH2:31][Br:32]>C(Cl)(Cl)(Cl)Cl>[CH3:21][O:22][C:23](=[O:33])[C:24]1[CH:29]=[C:28]([Br:1])[CH:27]=[CH:26][C:25]=1[CH2:31][Br:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(Br)c1CBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 25 °C

Procedure:
The mixture of 3- and 5-bromo-2-methylbenzoic acid methyl ester (35.79 g; 156 mmol) is dissolved in carbon tetrachloride (200 mL). To the solution is added N-bromosuccinimide (29.5 g; 166 mmol), followed by AIBN (54 mg) and the mixture was heated at reflux temperature for 20 hours. Then the mixture was cooled to room temperature and the succinimide was filtered from solution and rinsed with carbon tetrachloride. The solvent was evaporated to yield a mixture of the title compound and 3-bromo-2-bromomethylbenzoic acid methyl ester (48.1 g; crude mass).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[O:19])[NH:16][C:15]1=[S:20]>CO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:20][C:15]1[C:14]([CH3:21])([CH3:13])[NH:18][C:17](=[O:19])[N:16]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: CC1(C)NC(=O)NC1=S
Agent: Cl
Solvent: CO
Product: CN(C)c1ccccc1CSC1=NC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Initially, 2.5 g of 2-dimethylaminobenzylchloride hydrochloride was added to a solution of 1.5 g of 5,5-dimethyl-4-thiohydantoin in 50 mL of methanol (MeQH). The reaction mixture was stirred for two hours at the room temperature and concentrated in vacuo. To the residue, there was added 100 mL of CHCl3. The residue was washed two times with 100 mL of aqueous solution of NaHCO3, dried over MgSO4 and concentrated in vacuo. The residue purified by column chromatography [CHCl3 :MeOH=100:1 (v/v)]. Recrystallized from diethyl ether gave the desired compound in the form of needle-like crystal. The yield of this compound was 2 g with a yield ratio of 69.1%, and the melting point was 160°-162° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O1CCCC1>[OH-].[OH-].[Pd+2].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[C:17]([OH:19])=[O:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCC[C@@H]1Cc1cc(F)cc(F)c1
Reaction time: 96 h

Procedure:
A mixture of (1S,2R)-2-(3,5-difluorophenylcarbonyl)cyclohexanecarboxylic acid (1 g, 3.7 mmol), 10% Pd(OH)2 on carbon (1 g), tetrahydrofuran (10 mL) and acetic acid (0.5 mL) was shaken under hydrogen atmosphere at 50 psi for 96 h. The reaction mixture was filtered through Celite®, and filtrate and evaporated to give (1S,2R)-2-(3,5-difluorophenyl-methyl)cyclohexanecarboxylic acid, as a white solid (0.9 g, 95%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[H-].[Na+].Cl[CH2:17][C:18](=O)[CH3:19]>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[C:9]2[C:18]([CH3:19])=[CH:17][O:13][C:8]=2[CH2:7]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1ccco1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-furyl)cyclohexane-1,3-dione (mp155-156° C.; 0.89 g) in DMF (18 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (15 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-furyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.23 g).
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][C@@H:3]([NH2:7])[CH2:2]1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.CS(O)(=O)=O>CN1CCCC1=O.C(#N)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:1]([NH:8][C:10]4[C:19]5[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=5)[N:13]=[CH:12][CH:11]=4)[CH2:2]3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: N[C@@H]1CCC[C@H](N)C1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: CS(=O)(=O)O
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Clc1ccc2c(N[C@@H]3CCC[C@H](Nc4ccnc5cc(Cl)ccc45)C3)ccnc2c1
Yield: 21.9 %

Procedure:
23.2 g of cis-cyclohexane-1,3-diamine and 80.5 g of 4,7-dichloroquinoline are reacted at 150° C. in 400 ml of N-methyl-2-pyrrolidone under argon for 24 hours. After cooling insoluble material is filtered off and the filtrate is treated with 600 ml of water. The separated crude product is introduced into 400 ml of water and 100 ml of glacial acetic acid. The mixture is extracted three times with 200 ml of ethyl acetate each time and then adjusted to pH 12 by the addition of 600 ml of 2N NaOH. The separated crystalline diamine is recrystallized from 270 ml of dimethylformamide, 20.1 g of pure product being obtained. This is converted into the dimethanesulphonate in 200 ml of boiling acetonitrile with 6.4 ml of methanesulphonic acid. 19.5 g of colourless crystalline salt, m.p.:>250° C., are obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([NH:8][C:9]([C:11]1[N:12]=[C:13](Br)[S:14][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO>[C:4]([NH:8][C:9]([C:11]1[N:12]=[C:13]([O:2][CH3:1])[S:14][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[O-]
Reactant: CC(C)(C)NC(=O)c1csc(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(=O)NC(C)(C)C)cs1
Yield: 98 %

Procedure:
At 25° C., 8.90 g of a 30% strength solution (49 mmol) of sodium methanolate in methanol was added to a solution of 12.00 (46 mmol) of 2-bromothiazole-4-carboxylic acid-tert.-butylamide in 150 ml of methanol. The mixture was boiled under reflux for four hours, the clear solution was evaporated down, the residue was taken up to 300 ml of diethyl ether and filtered, and the solvent was removed under reduced pressure. There was obtained 9.60 g (98%) of the product as a yellow oil.