Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[H][H]>CC(O)=O.[Pt](=O)=O>[ClH:1].[CH3:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH:8]1[C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccncc1C(=O)O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCNCC1C(=O)O
Yield: 112.9 %

Procedure:
4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) and platinum (IV)oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL) under about 60 psi hydrogen for about 72 h at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to give 4-methylpiperidine-3-carboxylic acid hydrochloride (7.4 g, contained residual AcOH) that was carried forward without additional purification. To a portion of the acid (1.0 g, 4.92 mmol) in 1,4-dioxane (10 mL) was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol). The mixture was stirred for about 10 min before adding Et2O (10 mL). The precipitate was collected by vacuum filtration was washed with Et2O (5 mL) to give a solid (0.27 g). To the filtrate was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol) and the mixture was concentrated under reduced pressure to constant weight, while adding DCM (20 mL) to the resulting residue to give a thick yellow oil (0.56 g). The two portions were combined to give 4-methylpiperidine-3-carboxylic acid hydrochloride (0.83 g, 93%). To the acid (0.83 g, 4.6 mmol) was added N-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.08 mmol), Na2CO3 (1.71 g, 16.2 mmol), and water:1,4-dioxane (1:1, 20 mL). The mixture was stirred at room temperature for about 16 h and the organic solvent was removed under reduced pressure. The aqueous phase was neutralized by the addition of 1N HCl. The solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were washed with brine and dried over anhydrous MgSO4. The solution was filtered and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 100%): LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z: 278 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16](I)[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.C[CH2:31][N:32](C(C)C)C(C)C.CN.C(Cl)Cl>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[C:16]([NH:32][CH3:31])[C:13]([C:14]#[N:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)c(I)c1C#N)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: ClCCl
Solvent: CCCCO
Product: CNc1c(F)c(Nc2cc(C3CC3)[nH]n2)nc(N[C@@H](C)c2ccc(F)cc2)c1C#N
Temperature: 185 °C
Yield: 51.4 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-4-iodonicotinonitrile (Example 134, 0.10 g, 0.19 mmol) and DIEA (0.03 g, 0.25 mol) in n-BuOH (1.5 ml) was added methylamine (2.0 M in THF, 1.9 mmol). The reaction was then heated to 185° C. under microwave conditions (1 hour×2 cycles). The reaction was then cooled to room temperature, DCM (10 ml) was added, and washed with 10% aqueous Na2S2O3. The organic layer was then dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.04 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.35 (br s, 2H), 7.04-7.00 (m, 2H), 5.95 (br s, 1H), 5.14 (br s, 1H), 3.15 (d, J=2.7 Hz, 3H), 1.87-1.82 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.94 (m, 2H), 0.65-0.63 (m, 2H). MS: Calcd.: 409; Found: [M+H]+ 410.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)=[O:8]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCSCC2)s1)c1ccncc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
Compound 588 (120 mg, 0.408 mmol) was dissolved in DMF (2 mL), and isonicotinic acid (150 mg, 1.22 mmol), EDC hydrochloride (234 mg, 1.22 mmol) and 1-hydroxybenzotriazole monohydrate (187 mg, 1.22 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 589 (106 mg, 65%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:25]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[C:16]([OH:15])[CH:24]=4)=[O:26])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CC#N
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography using Kiesel gel 60 as adsorbent (Merck) and toluene:methanol 4:1 as eluent. Mp.: 180-182° C. (toluene)
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][OH:15].[H-].[Na+]>>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[N:3]=1
Reactant: OCCc1cccc(Cl)c1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Clc1cccc(CCOc2cncc(Cl)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol) and m-chlorophenethyl alcohol (515 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). The crude product (0.92 g) was used directly in the next step. MS m/z 269 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C.[N-:18]=[C:19]=[O:20].[K+]>O>[NH:1]([CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:19]([NH2:18])=[O:20]
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NCCNc1ccc([N+](=O)[O-])cc1
Yield: 73.6 %

Procedure:
37 g (0.2 mole) of para-[N-(β-amino-ethyl)]amino nitrobenzene is dissolved in 200 cm3 of water at 30° C, to which 15 cm3 (0.26 mole) of acetic acid had been added. 17 g (0.21 mole) of potassium isocyanate is then rapidly added. The desired product precipitates immediately in a form which is very difficult to dry. 150 cm3 of acetic acid is added to the reaction mixture and it is heated until the urein is completely dissolved. After slow cooling, drying yields 33 g of para-[N-(β-ureidoethyl)]amino nitrobenzene in a well crystallized form, which is practically prue and melts at 187° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:10])([CH3:9])[C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:5]([CH3:7])([CH3:6])[C:4](=[O:8])[C:3]([CH3:10])([CH3:9])[CH2:2][OH:1]
Reactant: CC(C)C(=O)C(C)(C)CO
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Br)C(=O)C(C)(C)CO
Reaction time: 8 h

Procedure:
To a stirred, refluxing solution of 69 g. (0.48 mole) of 1-hydroxy-2,2,4-trimethylpentan-3-one in 500 ml. of chloroform was added dropwise a solution of 77 g. (0.48 mole) bromine in 100 ml. of chloroform. When the addition was completed the mixture was stirred at reflux for one hour, allowed to cool and stand overnight at room temperature. Evaporation of solvent at reduced pressure afforded 127 g. of product which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.I[C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[N:30]([C@H:38]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:29]=[C:28]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=5[N:6]=4)=[CH:15][CH:14]=3)[C:36]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccc(Cl)cc6s5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
Procedure for Suzuki coupling: A mixture of N-(6-chloro-1,3-benzothiazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.116 g, 0.30 mmol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.106 g, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.012 mmol) in ethylene glycol dimethyl ether (3.0 mL), sodium carbonate (0.064 g, 0.60 mmol), and water (1.5 mL) in a sealed Schlenk flask were heated at 90° C. for 24 h. The mixture was cooled, diluted with water (10 mL) and extracted with methanol/dichloromethane (1:19, 3×20 mL). The combined organic fractions were dried (magnesium sulfate), filtered, concentrated and purified by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.8-10.0 min) to afford cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-chloro-1,3-benzothiazol-2-amine as a yellow powder (0.036 g, 0.062 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.42 min;
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:15]=1[NH2:16].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:16]/[C:15]1[C:17]([Cl:24])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=1[Cl:13])=[N+:2]=[N-:3]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (3.00 g, 18.07 mmol) and 2,6-dichloro-4-nitroaniline (3.74 g, 18.07 mmol) in DCM (60 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (7.56 mL, 54.2 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 10.8 mL, 10.8 mmol). The reaction mixture was stirred at 0° C. for 3 hours, then allowed to reach room temperature over 1 hour. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the crude title compound as a yellow/brown solid (5.89 g, 92% yield). LCMS (Method C): RT=4.08 min, m/z: 327 [M+H+−N2].
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.O>O1CCCC1>[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33][N:2]([CH3:1])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: CNC(=O)c1ccncc1-c1ccccc1C
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cnccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 226 mg (1 mmol) N-methyl-3-o-tolyl-isonicotinamide in 10 ml tetrahydrofuran were added dropwise 1.3 ml (1.3 mmol) 1M potassium hexamethyldisilazide solution in tetrahydrofuran at room temperature. The white suspension was stirred for 30 min at room temperature and 0.18 ml (1 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added at the same temperature. The light brown suspension was stirred for 1 h and water was added. The aqueous layer was separated and washed with ethyl acetate. The combined organic layers were washed twice with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 440 mg (97%) of the title compound as a light brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1[CH:22]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][C:21]=1/[CH:22]=[CH:2]/[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 7.9 %

Procedure:
A solution of (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 226 mg, 0.878 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-ylbenzaldehyde (Ex-38B, 216 mg, 0.922 mmol) in DMF (8.0 mL) and MeOH (3.6 mL) was treated with lithium methoxide (140 mg, 3.69 mmol) and stirred for 21 h at room temperature under nitrogen. The reaction mixture was quenched with water (10 mL) and extracted ethyl acetate (2×20 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (6×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a red solid. Precipitation from dichloromethane (5 mL) gave the title compound (33 mg, 8%) as a brown solid, mp 155–158° C. 1H-NMR (300 MHz, DMSO-d6) 12.06 (br s, 1), 8.22 (m, 3H), 8.04 (d, 1H, J=15.3 Hz), 7.89 (d, 2H, J=7.8 Hz), 7.64 (d, 1H, J=15.3 Hz), 7.18 (s, 1H), 6.67 (s, 1H), 3.86 (s, 6H), 3.29 (br s, 2H), 3.16 (br s, 4H), 1.82 (br s, 4H). HRMS (ESI) Calcd. for C23H26N2O7S: 475.1539 [(M+H)+]; Found: 475.1547.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:18]1([S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Trifluoroacetic acid (3 ml) was added in one portion to a solution of 4-(4-Acryloylamino-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.23 g, 3.11 mmol) in DCM (6 ml). The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After which time, the mixture was concentrated under vacuum to give the title compound (0.9 g, 98% yield) as an orange foam which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.C[Mg+].[Br-].[Cl:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1.CCOC(C)=O>[Cl:31][CH2:32][C:33]([N:14]([C:12]1[C:11]([C:19]#[N:20])=[CH:10][C:9]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:34]
Reactant: CC(C)CNc1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reactant: O=C(Cl)CCl
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)CCl)c1nc(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Reaction time: 0.08 h

Procedure:
To the product of Step A EXAMPLE 27 (300 mg) in THF (5.0 mL) was added MeMgBr (0.92 mL, 1.4 M solution in toluene/THF 3:1) at 0° C. The reaction stirred for 5 minutes before adding chloroacetyl chloride (0.08 mL). The reaction stirred about 7 hours and was diluted with EtOAc, washed with 2 M aqueous HCl and brine. The dried solution (Na2SO4) was concentrated and purified via flash chromatography on silica gel gradient eluted with 0-15% EtOAc in hexane affording the title compound. HPLC/MS: 471.9 (M+1), 473.9 (M+3); Rt=4.32 min.
Reaction SMILES: [N+:1]([C:4]1[N:8]2[N:9]=[C:10]([S:13]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[N+:1]([C:4]1[N:8]2[N:9]=[C:10]([SH:13])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2ccc(SC(c3ccccc3)(c3ccccc3)c3ccccc3)nn12
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnc2ccc(S)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of 1.0 g (2.28 mmol) of 3-nitro-6-tritylsulfanylimidazo[1,2-b]pyridazine in 10 ml of anhydrous dichloromethane is treated with 0.73 ml (4.56 mmol) of triethylsilane and 1.0 ml (13 mmol) of trifluoroacetic acid under an argon atmosphere and stirred at room temperature for 3 h. 10 ml of 2N sodium hydroxide solution is then added and the mixture is extracted with 3×20 ml of ethyl acetate. The aqueous phase is then adjusted to pH 2 using hydrochloric acid and subsequently extracted with 3×20 ml of ethyl acetate. The organic extracts are washed with 20 ml of water, dried over magnesium sulfate and concentrated. The residue is crystallized by addition of a little diethyl ether. 0.34 g (76%) of the title compound is isolated as a pale yellow solid. M.p. 175-177° C.
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29]>CS(C)=O.O>[N:4]1([CH2:3][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:1][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: COc1ccc(COCC(O)Cn2ccnc2)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (20 g, 0.076 mol) was added to a stirred suspension of powdered potassium hydroxide (17 g, 0.30 mol) in dimethylsulphoxide (50 ml) at 18° C. and stirred for 0.5 hours. Ethyl 6-bromohexanoate (33.45 g, 0.15 mol) was then added and the resulting mixture was stirred at 18° C. for 12 hours. The reaction mixture was diluted with water (21) and washed with dichloromethane (2×100 ml), neutralised to pH 6-7 with sulphuric acid (2M) and extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which by column chromatography (silica gel, 20% methanol in ethyl acetate) gave pure 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid as a colourless oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[NH:7]/[C:6]/1=[N:15]\[NH2:16])[CH2:2][CH2:3][CH3:4].[CH:17]([O-])([O-])OCC>>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:17]=[N:16][N:15]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC([O-])[O-]
Reactant: CCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Product: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Temperature: 100 °C
Yield: 71.8 %

Procedure:
The mixture of (2E)-3-butyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (200 mg, 0.0009 mol) in Ethyl orthoformate (5 mL, 0.03 mol) was heated at 100° C. overnight. After cooling to room temperature, the reaction mixture was filtrated and dried to give the desired product (150 mg, 71.8%). LCMS calculated for C10H13N6O (M+H): 233.1; found: 233.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[C:10](O)(=O)[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:10]([CH3:11])=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: CC(=O)O
Reactant: NNc1cc(Br)ccn1
Product: Cc1nnc2cc(Br)ccn12
Temperature: 125 °C

Procedure:
To a vial flushed with argon was added 4-bromo-2-hydrazinylpyridine (1.88 g, 10 mmol) and acetic acid (2.5 mL). The mixture was refluxed at 125° C. under argon for 16 hours. After cooling to room temperature, acetic acid was distilled off, and to the residue was added saturated NaHCO3 (150 mL) and DCM (150 mL). The aqueous layer was extracted with DCM, the organic extracts were combined, dried over MgSO4, and concentrated to give the product. 1H NMR (400 MHz, CDCl3) δ 7.95-7.90 (m, 1H), 7.73 (d, J=7.3 Hz, 1H), 6.94 (dd, J=7.3, 1.7 Hz, 1H), 2.74 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C(C)C>[CH3:6][CH:7]([CH3:14])[CH2:8][NH:3][C:4]1[S:5][CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1csc(N)c1C(=O)OCC
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)C(=O)O
Product: CCOC(=O)c1csc(NCC(C)C)c1C(=O)OCC
Reaction time: 16 h
Yield: 172.4 %

Procedure:
Sodium borohydride (18 g) was added portionwise over 5 hours to a stirred suspension of diethyl 2-aminothiophene-3,4-dicarboxyate (33 g) in isobutyric acid (300 ml) at room temperature. The mixture was stirred for 16 hours then further sodium borohydride (4 g) was added and stirring was continued for 5 hours. Water (1.51) was added, the mixture was neutralised by addition of solid sodium bicarbonate and then extracted with ether (3×500 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to give the subtitle compound (35 g) as a solid.