Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=O>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2,6-Difluorobenzoyl chloride (1.28 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCNC1CCCCC1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of cyclohexanone (10 g, 0.10 mol) in Toluene (100 ml) was treated with 2-methoxy ethylamine (8.4 g, 0.11 mol) and refluxed at 110° C. for 3 h. The reaction mass was cooled and diluted with ethanol (50 ml) and sodium borohydride (5.8 g, 0.15 mol) was added in portions at 0° C. The reaction mass was stirred at RT for 12 h and concentrated under reduced pressure. The residue was dissolved in water (100 ml), extracted with DCM (2×100ml), dried over sodium sulphate and evaporated. The crude material was purified by column chromatography by using DCM and methanol (98:2) as eluent to afford the title compound as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:13]=1[C:14]#[N:15]>>[F:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1cc(O)ccc1F
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1cc(Oc2ccc(C=O)cc2F)ccc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde (188 mg, 1.32 mmol) and 2-fluoro-5-hydroxybenzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=2[CH:17]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[OH:35].[F-].[Cs+]>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:35][C:21]1[CH:22]=[CH:23][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[C:11](=[O:12])[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[NH:7][C:6]=3[CH:17]=2)=[CH:25][C:20]=1[O:19][CH3:18]
Reactant: O=C1Nc2ccccc2Nc2cc(Br)ccc21
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(-c2ccc3c(c2)Nc2ccccc2NC3=O)ccc1O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of Example 9 (116 mg, 0.4 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (150 mg, 0.6 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), and CsF (121 mg, 0.8 mmol) in DME (20 mL) and methanol (10 mL) was heated to reflux for 16 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 0.108 g (81%) of the desired product. MS (DCI) m/e 333 (M+H)+, 350 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.24 (d, J=1.8 Hz, 1H), 7.15-7.18 (m, 2H), 7.08 (dd, J=8.1, 1.5 Hz, 1H), 6.97-7.02 (m, 5H), 3.86 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:29]=[CH:28][N:27]([CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:31]([CH:30]([N:27]1[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][CH:16]=3)[N:22]=[CH:23][C:24]=2[CH:29]=[CH:28]1)[CH2:33][CH3:34])[CH3:32]
Reactant: CCC(CC)n1ccc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)n1ccc2cnc(Nc3ccc(N4CCNCC4)cc3)nc21
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 4-{4-[7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (167 mg, 0.36 mmol) in dichloromethane (3 mL) is added trifluoroacetic acid (1 mL). The reaction mixture is stirred for 1 h and concentrated in vacuo. The residue is diluted with dichloromethane, washed with NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo. Purification by preparative HPLC afforded 130 mg of [7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-(4-piperazin-1-yl-phenyl)-amine as a yellowish solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Br:26])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Br:26])=[CH:14][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 86.7 %

Procedure:
A flask was charged with 2,4-bis-benzyloxy-5-bromobenzoic acid (12.4 g; 30 mmol) and tetrahydrofuran (200 mL) and stirred under nitrogen until the solution was homogeneous. Lithium aluminum hydride (1.425 g; 1.25 eq.) was slowly added and the reaction was stirred until TLC indicated that the starting material had been consumed. The reaction was slowly quenched with a saturated solution of sodium sulfate (20 mL) and then filtered through celite. The solid was washed with an additional charge of tetrahydrofuran (100 mL), and the organic layers were evaporated to give 2,4-bis-benzyloxy-5-bromobenzyl alcohol (10.5 g; 26 mmol).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][NH:10][C:11](=O)[C:6]=2[CH:5]=1.O=P(Cl)(Cl)[Cl:18]>CN(C=O)C>[Cl:18][C:11]1[C:6]2[CH:5]=[C:4]([CH2:3][C:2]([F:15])([F:14])[F:1])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=c1[nH]cnc2sc(CC(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1cc2c(Cl)ncnc2s1

Procedure:
5.7 g of 6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one was added to 16 mL of POCl3 with one drop of DMF. The heterogeneous mixture was refluxed for 3 hs and then evaporated. The residue was quenched with ice and saturated ammonia solution and extracted with chloroform. Combined extracts were evaporated with silica gel and loaded on a short silica gel column. The column was eluted with hexane-ethyl acetate (5:1) to afford 5.9 g of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine. 1H NMR CDCl3 (300 MHz): 8.86 (s, 1H), 7.39 (s, 1H), 3.76 (q, 2H, J9.9 Hz). 13C NMR CDCl3 (75 MHz): 169.0, 154.7, 153.2, 129.9, 125.3, 123.5, 121.3, 35.9 (q, J33.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]#[C:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=3)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]>CO.C(O)(=O)C.[Pd]>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[N:16]=[C:15]([NH:18][C:19]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:26]=3)=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(C#Cc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(CCc2ccccc2)c1
Yield: 9.1 %

Procedure:
20 mg of (0.44 mmol) of 2-[(5-phenylethynyl-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide was dissolved in a mixture of 10 mL of CH3OH and 0.5 mL of acetic acid. To this stirring solution 10 mg of 10% Pd on carbon was added and the resulting mixture was hydrogenated (1 atm) at room temperature for 3.0 h. The reaction mixture was filtered, and the solid was washed with portions of methanol. The filtrate and washings were combined and evaporated to give 18 mg (88%) of 2-[(5-phenethyl-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 452 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:21]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1ccc(N)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)CCCl)cn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (1.00 g, 8.4 mmol) in dry dichloromethane (10 mL) was added triethylamine (1.27 g, 12.6 mmol) and the reaction mixture was stirred at 0° C. To the reaction mixture 3-chloropropionyl chloride (1.42 g, 12.6 mmol) was added drop wise over a period of 15 minutes, and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified over silica gel using methanol/chloroform as eluent. The pure fraction was concentrated to obtain 3-chloro-N-(6-cyanopyridin-3-yl)propionamide. To a solution of potassium hydroxide (0.1 g, 1.5 mmol) in dry methanol (20 mL) was added hydroxylamine hydrochloride (0.105 g, 1.5 mmol) and the mixture was stirred for 30 minutes. White precipitate of potassium chloride obtained was filtered and to the filtrate was added 3-chloro-N-(6-cyanopyridin-3-yl)propionamide (0.209 g, 1.0 mmol) as obtained herein above, and the reaction mixture was stirred at reflux temperature for 4 hours. The reaction mixture was then concentrated and the crude product obtained was triturated with diethyl ether to obtain a solid which was crystallized from ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[N:41]=[C:40]([Cl:42])[CH:39]=[C:38]([CH3:43])[C:34]=1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:42][C:40]1[CH:39]=[C:38]([CH3:43])[C:34]([C:35]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:8][CH2:7]2)[CH3:5])=[O:36])=[C:33]([CH3:32])[N:41]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Following General Procedure C: To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 0.31 mmol) and 2,4-dimethyl-6-chloronicotinic acid (68 mg, 0.31 mmol) in DMF (4 mL) was added DIPEA (0.8 mL), HOBT (75 mg, 0.56 mmol) and EDCI (89 mg, 0.46 mmol) and the reaction stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH,) gave 42 mg (23%) of the title compound as a white solid: 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz) 1.07-1.32 (m, 2H), 1.53-1.61 (m, 1H), 1.83-1.91 (m, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 2.48 (s, 3H, 2.76-2.91 (m, 3H), 3.26-3.39 (m, 3H), 3.43 (s, 3H), 3.68-3.71 (m, 2H), 3.73-3.82 (m, 1H), 4.01-4.04 (m, 4H), 6.64 (d, 2H, J=9 Hz), 6.76 (d, 2H, J=9 Hz), 6.98 (s, 1H), 7.03 (d, 1H, J=6 Hz), 7.97 (br s, 1H), 8.26 (s, 1H), 8.29 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.60, 19.19, 22.52, 29.68, 30.58, 31.80, 39.70, 44.36, 47.79, 59.57, 60.04, 68.06, 71.53, 115.72, 120.29, 122.88, 125.50, 148.34, 149.57. ES-MS m/z 594 (M+H). Anal. Calcd. for C33H44N5ClO3.0.2CH2Cl2: C, 65.24; H, 7.32; N, 11.46. Found: C, 64.88; H, 7.36; N, 11.54.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]1=[O:13])=[O:6].[OH-:15].[Na+]>>[O:6]=[C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:14])[CH2:7][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:13])=[O:15]
Reactant: [OH-]
Reactant: CC(C)CCC(=O)C1CCCCC1=O
Agent: [Na+]
Product: CC(C)CCC(=O)CCCCCC(=O)O

Procedure:
10 g of 2-(4'-methyl valeryl) cyclohexanone are added to 70ml of a 5% aqueous solution of sodium hydroxide. The mixture is heated under reflux for 2 hours. The aqueous solution is then made acidic with a 4 N solution of hydrochloric acid and is extracted with ether. The ethereous phase is separated, is washed with a saturated solution of sodium chloride, is dried on sodium sulphate, is filtered and is evaporated to dryness. The solid residue weighing 9g is left to stand at room temperature. The crystallization begins quickly. The crystals are recovered and are recrystallized from n- pentane (yield 6.2g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:19][O-:20].[Na+].O>CO>[Br:1][C:2]1[C:3]([N:9]([CH2:16][CH:17]=[CH2:18])[C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: C=CCN(C(=O)C(C)(C)C)c1nc(Cl)ccc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CCN(C(=O)C(C)(C)C)c1nc(OC)ccc1Br
Yield: 89.3 %

Procedure:
A solution of N-(3-bromo-6-chloro-2-pyridinyl)-2,2-dimethyl-N-2-propen-1-ylpropanamide (12.388 g, 37.370 mmol) in methanol (100 ml) at rt under argon was treated with sodium methoxide solution (25% w/v in methanol, 17.76 g, 82.212 mmol) and then heated at reflux for 42 h. The reaction was then cooled, treated with water (500 ml), and extracted with diethyl ether (3×200 ml). The organic extracts were dried (MgSO4), and evaporated to give the product (10.918 g, 89%).
Reaction SMILES: BrBr.[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:15]=[C:14]2[C:9]([NH:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[S-:19][C:20]#[N:21].[K+]>C(O)(=O)C>[NH:21]=[C:20]1[N:10]2[CH2:11][C:12](=[O:16])[NH:13][C:14]3[CH:15]=[C:6]([O:5][C:4]([F:3])([F:17])[F:18])[CH:7]=[C:8]([C:9]=32)[S:19]1
Reactant: O=C1CNc2ccc(OC(F)(F)F)cc2N1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N=c1sc2cc(OC(F)(F)F)cc3c2n1CC(=O)N3
Yield: 15.1 %

Procedure:
The procedure is carried out as in Example 23, but starting with 1.1 g of bromine in 3.5 ml of acetic acid, 1.6 g of 7-trifluoromethoxy-3,4-dihydro-1H-quinoxalin-2-one and 1.54 g of potassium thiocyanate in 20 ml of acetic acid. The product obtained (1.8 g) is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol (99-1 by volume). 0.3 g of 2-imino-8-trifluoromethoxy-2H,4H-thiazolo[3,4,5-de]quinoxalin-5(6H)-one is thus obtained in the form of-a yellow solid melting at 255° C. [Analysis C10H6F3N3O2S, % calculated C: 41.53, H: 2.09, F: 19.71, N: 14.53, O: 11.06, S: 11.09, % found C: 41.00, H: 1.7, F: 19.2, N: 14.50, S: 11.6].
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([CH:9](Br)Br)[C:4]=2[CH:3]=1.[NH2:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][CH:7]=[C:8]([CH:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][C:15]([CH3:22])=[C:16]3[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: Brc1ccc2scc(C(Br)Br)c2c1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1csc2ccc(Br)cc12
Yield: 28.2 %

Procedure:
A mixture of 2.35 g of 5-bromo-3-(dibromomethyl)benzo[b]thiophene and 1.6 g of ethyl 3-aminocrotonate in 4 ml of ethanol was heated to reflux for 14 hours. The mixture was evaporated in vacuo and the residue was purified by chromatography over silica gel to provide 0.8 g of the desired title product, m.p. 68°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:7][CH:8]=1.C(N(CC)CC)C.Cl.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[N:5][CH:4]=1
Reactant: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cnc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of 4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (8-4, 0.41 g, 1.23 mmol) in CH2Cl2 (6.0 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered, and recrystallized in toluene to give N-(4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (8, 0.37 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1 H), 8.80 (d, J=4.9 Hz, 2 H), 8.42 (s, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J=7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J=6.5 Hz, 2 H), 0.32 (d, J=5.7 Hz, 2 H). ESI-MS: m/z 433.8 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:17])[NH:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]1.Cl.[N:19]([O-])=[O:20].[Na+]>>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5](=[O:17])[NH:6][CH:7]1[CH2:8][C:9]([CH3:16])([CH3:15])[NH:10][C:11]([CH3:13])([CH3:14])[CH2:12]1
Reactant: CC1(C)CC(NC(=O)NCCCl)CC(C)(C)N1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC1(C)CC(NC(=O)N(CCCl)N=O)CC(C)(C)N1
Reaction time: 1.5 h

Procedure:
To a solution of 1 g. of 4-[3-(2-chloroethyl)ureido]-2,2,6,6-tetramethylpiperidine in 8 ml. of 10% hydrochloric acid was added gradually 0.4 g. of sodium nitrite at 0° - 5° C. After completion of the addition, the reaction mixture was stirred at a temperature below 10° C. for additional 1.5 hours. The crystalline substances separated out in situ during the stirring were recovered by filtration, washed with a small amount of cold water and recrystallized from aqueous methanol to give 0.5 g. of the pure hydrochloride.monohydrate of the desired product having pale yellow color and a decomposition point of 159° - 163° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].[NH2:11][CH:12]([CH:14](N)[CH3:15])[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([CH3:10])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]1[NH:11][CH:12]([CH3:13])[CH:14]([CH3:15])[N:8]=1
Reactant: CC(N)C(C)N
Reactant: Cc1nn(C)c(C#N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nn(C)c(C2=NC(C)C(C)N2)c1N
Yield: 91.7 %

Procedure:
A mixture of 7 g (0.05 mol) of 4-amino-5-cyano-1,3-dimethylpyrazole, 5 g (0.057 mol) of 2,3-diaminobutane and 10.5 g (0.055 mol) of p-toluene sulfonic acid hydrate is heated in an oil bath at 180°-200° C. for seven hours. The yellow melt is dissolved in 200 ml of chloroform and stirred with 100 ml of 20% aqueous sodium carbonate solution. The organic layer is separated, dried over MgSO4 and evaporated in vacuo to give 9.5 g of 2-(4-amino-1,3-dimethyl-5-pyrazolyl)-4,5-dimethylimidazoline and characterized as a dihydrochloride salt, mp 250° C. from 20% isopropanolic HCl and ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][C:3](=[CH2:32])[C:4]([N:6]([CH:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])CC1C=CC(OC)=CC=1OC)=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3](=[CH2:32])[C:4]([NH:6][CH:18]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])=[O:5]
Reactant: C=C(CBr)C(=O)N(Cc1ccc(OC)cc1OC)C(CC(C)C)C(=O)NCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CBr)C(=O)NC(CC(C)C)C(=O)NCC(=O)OCC
Reaction time: 1 h

Procedure:
Compound 1 (117 mg, 0.23 mmol) was dissolved in methylene chloride (2 ml). Next, this was supplemented with trifluoroacetic acid (475 μl) at room temperature. The mixture was left for 1 hour while observing the colour change from clear to dark violet. The flask contents were transferred into a separator, and this was supplemented with methylene chloride (4 ml) and a saturated solution of sodium carbonate was added until the disappearance of the violet colour. The aqueous phase was extracted with methylene chloride (3×8 ml), and then the combined organic phases were dried with brine and the solvent was evaporated off. The remainder was purified using column chromatography in a hexane: ethyl acetate system (silica gel, Rf=0.25, 6:4, v:v).
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][C@@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:8]2)[CH2:4][C@H:3]1[NH:14][C:15]1[C:16]2[N:17]([CH:24]=[C:25]([C:27]3[N:28]=[N:29][N:30]([CH3:34])[N:31]=3)[CH:26]=2)[N:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn[nH]3)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnn(C)n3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude 4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-6-(1H-tetrazol-5-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide from Step 2, iodomethane (6.8 μl, 0.109 mmol) and potassium carbonate (23.2 mg, 0.168 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was stirred at room temperature for 2 h. Attempted purification by RP-HPLC gave impure product. The mixture was further purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane to give the title compound (4 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (d, J=7.3 Hz, 1H), 8.30 (s, 1H), 8.20 (d, J=1.5 Hz, 1H), 7.40 (d, J=1.5 Hz, 1H), 5.91-5.90 (m, 1H), 4.40 (s, 3H), 4.28-4.05 (m, 1H), 3.35-3.13 (m, 4H), 2.93 (s, 3H), 2.90-2.75 (m, 1H), 2.62-2.55 (m, 1H), 2.46-2.30 (m, 1H), 1.66-1.54 (m, 1H), 1.39-1.29 (m, 1H), 1.08 (d, J=6.6 Hz, 3H); MS (ES+) m/z: 460.3 (M+H); LC retention time: 6.988 min (analytical HPLC Method E).