Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+:8].[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1>C(O)C>[Na+:8].[Br:9][C:10]1[N:15]=[CH:14][C:13]([CH:16]=[CH:4][C:2](=[O:3])[C:1]([O-:6])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=O)C=Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of pyruvic acid (412.0 uL, 5.9 mmol) in ethanol (0.6 mL) was added to a 0.5 M sodium hydroxide solution (16.1 mL). The reaction mixture was stirred at room temperature for 10 minutes and then a solution of 6-bromo-3-pyridinecarbaldehyde (1.0 g, 5.4 mmol) in ethanol (5.4 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid was washed with diethyl ether to give 1.3 g of 4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid sodium salt as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:11])[N:7]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[C:6]=2[CH:24]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:19]1[N:18]=[C:17]([N:7]2[C:6]3[CH:24]=[C:2]([C:34]#[C:33][C:31]([C:28]4[CH:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(C(=O)N3CCCC3)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(C(=O)N4CCCC4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.3 %

Procedure:
A mixture of 4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (200 mg, 0.49 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (350 mg, 0.50 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred under nitrogen at 70° C. for 2 hr. The reaction mixture was cooled to room temperature and purified on a C18 column (acetonitrile/water, 5:95-80:20) to afford 88 mg (38%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a light yellow solid. 1H NMR (300 MHz, DMSO) delta 8.42 (d, J=5.1 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.03 (s, 2H), 6.74 (d, J=5.1 Hz, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 3.61 (d, J=6.6 Hz, 2H), 3.48 (d, J=6.6 Hz, 2H), 2.40 (s, 3H), 1.92 (s, 4H), 1.80 (s, 3H); LC-MS: m/z=+458 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2nc3ccc(F)cc3nc2OC)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 82%). 1H NMR (200 MHz, CDCl3): δ 3.14-3.17 (m, 4H), 3.78-3.81 (m, 4H), 3.88 (s, 3H), 4.14 (s, 3H), 6.88-7.41 (m, 7H), 7.81 (dd, J=9.0 and 5.7 Hz. 1H).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:35]=[CH:34][C:21]([O:22][CH2:23][C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>O>[C:36]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)N(Cc2ccccn2)C(C)=O)cc1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
A mixture of 0.70 g of product from Example 88, 2.96 g of acetic anhydride, 0.027 g of 4-N,N-dimethylaminopyridine and 15 ml of pyridine is heated at 110° C. for 35 hours and at reflux temperature for 57 hours. The reaction is poured into water and extracted with methylene chloride. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 0.366 g of product as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[C@H:22]([CH3:23])[CH2:21][O:20][C@H:19]([C:24]([NH:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1[F:27])#[N:2]
Reactant: Nc1ccccc1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)O)OC[C@H]2C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)Nc3ccccc3)OC[C@H]2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A mixture of (2S,5R)-4-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinecarboxylic acid (300 mg, 0.81 mmol), HATU (340 mg, 0.89 mmol), and Hünig's base (0.21 mL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 10 minutes. Aniline (0.085 mL, 0.93 mmol) was then added, and stirring continued at room temperature for 17 hours. LC-MS indicated about 50% conversion, so another portion each of Hünig's base (0.21 mL, 1.20 mmol) and HATU (340 mg, 0.89 mmol) were added. After about 10 minutes more aniline (0.085 mL, 0.93 mmol) was added, and the mixture was stirred for an additional 1.5 hours. It was then diluted with EtOAc (25 mL) and washed successively with water, saturated aqueous NaHCO3, and brine (25 mL each). The organic phase was then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g SiO2, 10-35% EtOAc in hexanes gradient) to give the title compound (340 mg, about 80% purity) as a yellow oil. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6](Cl)=[O:7])(=O)C.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:22])([P:18]([OH:21])(=[O:20])[OH:19])[P:14]([OH:17])(=[O:16])[OH:15].[OH-].[Na+:24]>O.CN(C=O)C>[Na+:24].[Na+:24].[Na+:24].[OH:4][CH2:5][C:6]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:22])([P:14]([O-:17])(=[O:15])[OH:16])[P:18]([O-:21])(=[O:19])[O-:20])=[O:7]
Reactant: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)NCCCC(O)(P(=O)([O-])[O-])P(=O)([O-])O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetoxyacetyl chloride (0.324 ml) is dropped into a solution of 4-amino-1-hydroxybutane-1,1-diphosphonic acid (500 mg) in water (5 ml) and1N NaOH (8 ml), simultaneously adding 1N NaOH (3 ml) to maintain pH between11 and 12. When the additions are completed, the reaction mixture is stirred at room temperature for 2 hours, then it is diluted with DMF: a precipitate separates which is recovered by centrifugation and purified byredissolution in water (3 ml) and reprecipitated with acetone (30 ml), to give 720 mg of N-(hydroxyacetyl)-4-amino-1-hydroxybutane-1,1-diphosphonic acid trisodium salt; m.p. >260°
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][C:21]([CH3:20])=[N:25][C:24]=3[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc2cc(C=O)ccc2s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2sc(C)nc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-methylbenzo[d]thiazole-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.78 min.; [M+H]+: 397.01 g/mol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH3:11].[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:28]([C:29]5[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=5)[N:27]=[CH:26][CH:25]=4)[CH:22]=3)[C:17]([CH2:36][CH3:37])=[N:16]2)[CH2:14][CH2:13]1.O.C(#N)C>CN(C)C=O>[CH:12]1([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:8][CH2:9][O:10][CH3:11])[CH:30]=5)[N:27]=[CH:26][CH:25]=4)[CH:22]=3)[C:17]([CH2:36][CH3:37])=[N:16]2)[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3cccc(O)c3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3cccc(OCCOC)c3)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
Potassium carbonate (60.2 mg, 4.36 mmol), and 1-bromo-2-methoxyethane (40.9 μl, 4.36 mmol) were added to a solution of 3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol (50 mg, 1.0 mmol) in N, N-dimethylformamide (3 mL), and the resulting mixture was stirred at 60° C. for 16 hours, then at 80° C. for a further 24 hours. After cooling, the reaction mixture was diluted by the addition of water/acetonitrile (1.0 mL), which was then filtered. The filtrate was purified by preparative HPLC (C18 column, 30×100 mm) using a gradient of 35-80% acetonitrile:water (with 0.1% formic acid) as the eluent at a flow rate of 45 mL/min to afford 24 mg (40%) of 1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole. LC/MS (EI) tR 4.3 (Method E), m/z 403.2 (M++1). 1H NMR (CDCl3) δ 1.0 (m, 4H); 1.4 (t, 3H); 3.0 (q, 2H) 3.5 (m, 4H); 3.7 (d, 2H); 4.1 (d, 2H) 6.6 (s, 1H); 6.8-6.9 (dd, 2H); 7.1 (m, 2H); 7.2 (m, 1H); 7.3 (s, 1H); 7.5 (d, 1H); 7.8 (s, 1H).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9])=[CH:3][CH:2]=1.[Br:15]Br.S(=O)(O)[O-].[Na+]>O>[Br:15][C:5]1[CH:6]=[C:1]([CH3:14])[CH:2]=[CH:3][C:4]=1[NH:7][C:8]([NH:10][C:11]([NH2:13])=[NH:12])=[NH:9]
Reactant: BrBr
Reactant: Cc1ccc(NC(=N)NC(=N)N)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NC(=N)NC(=N)N)c(Br)c1

Procedure:
To a slurry of 10 g. (0.0523 mole) of 1-(p-tolyl)biguanide in 175 ml of water is added dropwise 8.4 g. (0.053 mole) of bromine over a period of 3 hours. The reaction mixture is cooled and the unreacted bromine discharged with sodium bisulfite. The mixture is made strongly alkaline and extracted into ether. The ether layer is dried over Na2SO4, charcoaled, filtered and evaporated to obtain 1-(2-bromo-4-methylphenyl)biguanide.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:5][CH2:4]1)[CH3:2]>[Pd].CCO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCN(c2ccc(N)nc2)CC1
Reaction time: 2 h
Yield: 111 %

Procedure:
In a hydrogenation bottle, 138a (2.59 g, 10.96 mmol), EtOH (100 mL), 10% Pd/C (580 mg, 0.55 mmol) were added. The mixture was hydrogenated at 55 psi for 2 hrs, and then filtered through celite and washed with MeOH (20 mL). The solvent was removed in vacuo and pink solids were obtained as 138b (2.51 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH2:23])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[NH:23][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Nc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A solution of 4-methoxy-3-nitro-benzoyl chloride (7.12 g, 33.0 mmol) in THF (50 ml) was added dropwise with stirring to a solution of 4-bromo-2-aminophenol (6.20 g, 33.0 mmol) in THF (50 ml) containing triethylamine (6.82 ml, 66.0 mmol). After addition was complete the reaction was stirred at room temperature overnight. The reaction mixture was concentrated to approximately half the original volume and the precipitate collected by filtration. The solid was washed with methanol and ether and dried under vacuum to give the subtitle compound as a brown solid (5.24 g, 42%). 1H NMR (DMSO) δ 8.58(d, 1H), 8.36(dd, 1H), 7.55(d, 1H), 6.96(m, 2H), 6.68(dd, 1H), 4.05(s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:9](OCC)=[O:10])[NH:8][C:4]=2[N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[C:7]([CH2:9][OH:10])[NH:8][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1cc2scnc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2scnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 4H-pyrrolo[2,3-d]thiazole-5-carboxylate (5 g, 25.48 mmol) and in anhydrous tetrahydrofuran (100 mL) was added lithium aluminum hydride (4.34 g, 127.5 mmol) dissolved in anhydrous tetrahydrofuran (50 mL) dropwise between −10° C. and 0° C. After the addition, the mixture was stirred below 0° C. for 1 hours, and then warm to the ambient temperature and allowed to stir for 3 hours at room temperature. The reaction mixture was cooled down to 0° C., quenched by 10 mL water, and then 10 mL 4N sodium hydroxide. The resulting white precipitate was filtered off, washed with acetic ester. The filtrate was dried by anhydrous sodium sulphate. The solvent was removed to afford the crude product (3.5 g, 89%). The crude product was used directly in the next step. LCMS (M+H) m/z: calcd. 154.02. found 154.9.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][C:12]1[N:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:28])([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:15][C:16]=1[CH3:17])C.C(OCC)(=O)C.[NH4+].[Cl-]>O1CCCC1>[CH3:17][C:16]1[S:15][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([F:29])([F:27])([F:25])([F:26])[F:28])=[CH:20][CH:19]=2)=[N:13][C:12]=1[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)Cc1nc(-c2ccc(S(F)(F)(F)(F)F)cc2)sc1C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccc(S(F)(F)(F)(F)F)cc2)nc1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
458 mg Lithium aluminium hydride were suspended in 100 ml dry tetrahydrofuran and cooled in an ice bath. To this ice cooled suspension were added 4.5 g [5-Methyl-2-(4-pentafluorosulfanyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester, dissolved in 50 ml tetrahydrofuran. The reaction mixture was stirred for one hour. Then 300 ml ethyl acetate and 20 ml saturated NH4Cl solution were added. The organic layer was separated. The aqueous phase was extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane:ethyl acetate=2:1 to provide 1.44 g 2-[5-methyl-2-(4-pentafluorosulfanyl-phenyl)-thiazol-4-yl]-ethanol as an oil which solidified upon standing.
Reaction SMILES: O[CH:2]=[CH:3][C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: CC1(C(=O)C=CO)CC2(CCC2)C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C(=O)/C=C/Cl)CC2(CCC2)C1
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A solution of 4.0 g of (2-methylspiro[3.3]hept-2-yl) (2-hydroxyvinyl) ketone in 25.0 ml of benzene was added dropwise with stirring to 3.95 g of thionyl chloride. The reaction mixture was allowed to stand for 18 hr at 25° C. The product was isolated by distillation (high vacuum) to afford 2.66 g 1-chloro-3-(2-methylspiro[3.3]hept-2-yl)-1E-propen-3-one as a yellow oil (40%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:6](=[N:11][C:12]3[C:17]([C:8]=2[Cl:25])=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1ccc2nc3c([N+](=O)[O-])ccc(Cl)c3c(Cl)c2c1

Procedure:
A stirred mixture of 12.9 of 6-chloro-2[(4-methoxyphenyl)amino]-3-nitrobenzoic acid, 25 ml of chlorobenzene and 50 ml of phosphorus oxychloride is heated to reflux temperature over a period of one hour, and held under reflux for 4.5 hours. The mixture is allowed to cool, the precipitate collected, providing the yellow title compound, mp 243-246 degrees after recrystallization from toluene.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[N:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:37])=[O:28])=[N:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 50 °C
Yield: 113 %

Procedure:
A mixture of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid that was prepared in a manner analgous to that described for Intermediate Example Int-27 (0.075 g, 0.16 mmol), cesium carbonate (0.15 g, 0.46 mmol, 3.0 equiv) and methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) in DMF (2 mL) was stirred at room temperature for 2 days, after which additional methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) was added and the mixture was heated at 50° C. for 3 h. The resulting mixture was treated with water (25 mL). The aqueous mixture was extracted with EtOAc (3×10 mL). The combined organics were dried (Na2SO4 anh) and concentrated under reduced pressure to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.087 g, 113%) which was used without further purification:
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1B(O)O.Br[C:33]1[C:34]([CH3:43])=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:43][C:34]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=[CH:42][C:33]=1[C:23]1[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:21]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: COC(=O)c1cccc(Br)c1C
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: COC(=O)c1cccc(-c2c(C)cccc2C)c1C
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a two-neck round bottom flask with a magnetic stirring bar, was added tris(dibenzylideneacetone)dipalladium(0) (120 mg, 0.131 mmol), tri-t-butylphosphonium tetrafluoroborate (76 mg, 0.262 mmol), cesium fluoride (2.65 g, 17.5 mmol), 2,6-dimethylphenylboronic acid (1.3 g, 8.73 mmol), and the compound from Step A (1 g, 4.4 mmol). One neck of the flask was connected to a vacuum line while another neck was fitted with a argon balloon. The flask was then purged 8-10 times with argon. The vacuum line was replaced with a septum and anhydrous THF (10 mL) was added by syringe. The mixture was stirred in a 70° C. oil bath for 16 h. The reaction solution was filtrated and concentrated. The residue was purified by column chromatography on silica gel Biotage 40S™, eluting with EtOAc/hexane (10:1) to give the title compound as a clear oil.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH3:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16](OC)=[O:17])=[N:11][CH:12]=1.[OH-].[Na+]>C1COCC1.ClCCl.O>[CH3:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:14]=[C:15]([CH2:16][OH:17])[CH:20]=[CH:21][CH:22]=2)=[N:9][CH:8]=1
Reactant: COC(=O)c1cccc(-c2ncc(C)cn2)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2cccc(CO)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
600 mg (5.41 mmol) of powdered calcium chloride are added to a suspension of 400 mg (10.6 mmol) of sodium borohydride in 20 ml of THF, and the mixture is stirred at room temperature for 1.5 hours. A solution of 751 mg (3.29 mmol) of methyl 3-(5-methylpyrimidin-2-yl)benzoate in 10 ml of THF is added dropwise to this suspension with stirring, and the mixture is stirred at room temperature for 18 hours. 10 ml of 1 N NaOH, water and dichloromethane are added to the reaction mixture, which is then filtered. The organic phase of the filtrate is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: [3-(5-methylpyrimidin-2-yl)phenyl]methanol as colourless solid; LCMS 201.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.Cl[C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:28])(=[O:27])[N:19]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.O1CCCC1.C(OC(=O)C)C>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[S:20](=[O:27])(=[O:28])[N:19]=3)=[CH:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2ccc(CNC3=NS(=O)(=O)c4ccccc43)o2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.1 %

Procedure:
An ice-cooling mixture of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (0.8 g), 3-chlorobenzoisothiazol-1,1-dioxide (0.8 g) and triethylamine (0.5 ml) in N,N-dimethylformamide (15 ml) was stirred for 3 hours. To a reaction mixture was added a mixture of ethylacetate, tetrahydrofuran and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and a residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 2-(diaminomethyleneamino)-4-[5-(1,1-dioxobenzoisothiazol-3-yl)aminomethylfuran-2-yl]thiazole (0.49 g).