Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(C(F)(F)F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (77 mg, 76%), MS (ISP) m/z=404.4 [(M+H)+], mp 278° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1

Procedure:
4-(Tert-butoxycarbonylamino-methyl)-benzoic acid was reacted with WSCI, HOBt, triethylamine and N-methylpiperazine in dichloromethane, to obtain a crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester, and then treated with TFA, to obtain (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-aminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (159 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid 4-(4-methyl-piperazine-1-carbonyl)-benzylamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-293) as a colorless powder (64 mg, 62%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]
Reactant: CCC=CCCO
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OCCC=CCC
Temperature: 125 °C
Yield: 82.2 %

Procedure:
Hex-3-en-1-ol (179 g), crotonic acid (181 g), PTSA (7.2 g), and toluene (250 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 4-5 hours until no more water evolved. The reaction mixture was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further distilled to provide but-2-enoic acid hex-3-enyl ester (247 g) with a boiling point of 109° C. at 20 mmHg.
Reaction SMILES: [O:1]([C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[O:1]([C:8]([CH3:13])([CH3:12])[C:9]([N:24]1[CH2:25][CH2:26][N:21]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:22][CH2:23]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccccc1)C(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Product: CC(C)(Oc1ccccc1)C(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.01 mol of 2-phenoxyisobutyric acid chloride (obtained by reaction of thionyl chloride with 2-phenoxyisobutyric acid) in 100 ml of methylene chloride is introduced into an Erlenmeyer flask containing a solution of 0.01 mol of 1-benzylpiperazine in 100 ml of methylene chloride. The mixture is stirred for 5 hours at room temperature, filtered and evaporated to dryness. The residue is taken up in water, basified and extracted with chloroform. The organic phases are combined, dried and evaporated.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][CH2:10][CH2:11][Cl:12])=[N:5][N:4]=[N:3]1
Reactant: ClCCCBr
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCCl
Yield: 111.4 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (4.6 g) and 1-bromo-3-chloropropane (9.4 g) are dissolved in acetone (100 ml). Potassium carbonate (6.8 g) is added to the solution and the mixture is refluxed for 3 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform and the chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by silica gel column chromatography (Wakogel C-200 made by Wako Jun Yaku Co., Ltd.). The column is eluted with benzene-ether (5:1, V/V) to obtain 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (8.5 g) as colorless liquid. nD14 =1.5396
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N:41]([CH2:45][CH2:46][Cl:47])[CH2:42][CH2:43][Cl:44])=[CH:37][CH:36]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd].O1CCOCC1>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:48])[CH2:32][CH2:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N:41]([CH2:42][CH2:43][Cl:44])[CH2:45][CH2:46][Cl:47])=[CH:39][CH:40]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCOC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% palladium on carbon (320.7 mg) was placed into an eggplant type flask (100 ml), followed by dropwise addition of 1,4-dioxane (15 ml) at 0° C. To this mixture was added a 1,4-dioxane (15 ml) solution of 1-[3-benzyloxy-1,3,5(10) -estratriene-17β-oxy]-2-[4-[p-[bis (2-chloroethyl)amino]-phenyl]-butyryloxy]ethane (I-5) dropwise at 0° C. The mixture was heated to room temperature and stirred under hydrogen gas for one hour. The reaction mixture was filtered through filter paper while washing with 1,4-dioxane, and the filtrate was concentrated under reduced pressure to produce an oily substance (0.27 g). It was purified by silica gel chromatography (hexane/ethyl acetate=3:1) to obtain 1-[3-hydroxy-1,3,5(10)-estratriene-17β-oxy]-2-[4-[p-[bis (2-chloroethyl)-amino]phenyl]butyryloxy]ethane (0.26 g) (Rf: 0.25, hexane/ethyl acetate=3:1) as oily substance.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18](I)[C:13]=3[O:12][N:11]=2)[CH2:8][CH2:7]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>O1CCCC1.O>[CH:6]1([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([B:20]([OH:25])[OH:21])[C:13]=3[O:12][N:11]=2)[CH2:8][CH2:7]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Ic1cccc2c(NC3CC3)noc12
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cccc2c(NC3CC3)noc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 2.83 mL, 5.7 mmol) was added dropwise over 20 minutes to a stirred solution of N-cyclopropyl-7-iodobenzo[d]isoxazol-3-amine (preparation 22 g, 0.50 g, 1.7 mmol) in tetrahydrofuran (10 mL) at −10° C. The mixture was stirred for 1 hour at 0° C. then triisopropyl borate (1.15 mL, 5.0 mmol) was added dropwise over 10 minutes and the mixture was stirred for 1 hour at 0° C. Then, the mixture was warmed to room temperature and stirred overnight. Water was then added, the mixture was cooled by means of an ice-water bath and the pH was adjusted to 1 with 2M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and the solid was filtered and dried to give the title compound (140 mg, 39%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)(=O)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl.[CH3:17][CH2:18][O:19]CC>>[CH3:11][C:7]1[CH:8]=[CH:9][C:10]([C:18]([CH3:17])=[O:19])=[C:5]([OH:4])[CH:6]=1
Reactant: CCOCC
Reactant: CC(=O)Oc1cccc(C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc(C)cc1O
Temperature: 165 °C

Procedure:
To 50 g (0.33 mol) of 3-acetoxytoluene from Step 1 was added AlCl3 (60 g, 0.45 mol) and the resulting mixture was heated at 165° C. for 20 min., then cooled to 0° C. and HCl 1N was carefully added followed by Et2O. The aqueous phase was extracted 5× with Et2O and the combined organic phase was washed with brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.[Cl-].ClC(Cl)(Cl)[C:27]([N:29]=C=O)=[O:28].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:27]([NH2:29])=[O:28])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)NC(N)=O)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) in methylenie chloride (1 mL) cooled to 0° C. was added trichloroacetyl isocyanate (50 μL, 0.42 mmol, 1.2 eq.). The mixture was stirred at 0° C. for 10 minutes and then methanol (10 mL) and a catalytic amount of Na2CO3 were added. The mixture was stirred at room temperature for 5 hours. The reaction was then concentrated. The reaction mixture was purified on silica gel eluting with ethyl acetate:hexane gradient (0-80%) to give the title compound (42 mg, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.66 (s, 1 H), 7.45-7.53 (m, 2 H), 7.32-7.40 (m, 2 H), 7.28-7.31 (m, 2 H), 7.02-7.06 (m, 2 H), 6.44 (d, J=8.09 Hz, 1 H), 5.42 (s, 2 H), 4.59-4.77 (m, 1 H), 3.79 (s, 3 H), 1.29 (d, J=6.99 Hz, 3 H); MS (DCI) m/z 370 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:3]=1[C:4]([NH:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[O:5]>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[NH2:16][C:13]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([CH:12]=1)[C:4]([NH:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[O:5]
Reactant: N#CC1(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#CC1(NC(=O)c2cc(N)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.15 g of iron powder are suspended in 18 ml of 5% strength acetic acid, and a solution of 3.0 g of 2-chloro-N-(1-cyanocyclopropyl)-5-nitrobenzamide in a mixture of 25 ml of ethyl acetate and 22.6 ml of glacial acetic acid is added. During the addition, the internal temperature is kept below 45° C. The reaction mixture is stirred at room temperature for 14 hours and then filtered through Celite. The filtrate is diluted with water, and the aqueous phase is extracted three times with ethyl acetate. The combined organic phases are washed twice with a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated on a rotary evaporator under reduced pressure. The crude product is triturated with a mixture of three parts of cyclohexane and one part of ethyl acetate, and the solid is filtered off. This gives 2.0 g (71%) of 5-amino-2-chloro-N-(1-cyanocyclopropyl)benzamide.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH:40](Cl)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:39][C@@H:40]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[S:4][CH2:3]2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(Cl)CCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 18.1 %

Procedure:
A mixture of 0.4 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 1 g of ethyl 4-(1-benzyloxycarbonyl-4-piperidyl)-2-chlorobutyrate, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile is heated under reflux for 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica-gel column chromatography (hexane:ethyl acetate=2:1) to give 0.15 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.25 g of tert-butyl 3(R)-[3-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpropyl]amino-4-oxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily material, respectively.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH3:24].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH3:24]
Reactant: COc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-135, 130 mg, 0.33 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4 methylmorpholine N-oxide (77 mg, 0.66 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:13])[CH:12]=[CH:16][N:17]([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)=O)cc1OC
Product: COc1ccc(C(=O)C=CN(C)C)cc1OC

Procedure:
A mixture of 50.0 g. of 3',4'-dimethoxyacetophenone and 50 ml. of dimethylformamide dimethylacetal is refluxed for 16 hours. On cooling the desired compound crystallizes from solution. Hexane is added and the material is recovered by filtration, m.p. 124°-125° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:28]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2)=[O:29]
Reactant: CN(C)C=O
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 29 mL of n-BuLi (1.6 M in hexane) in 40 mL of dry tetrahydrofuran under a nitrogen atmosphere at −78° C. was added dropwise a solution of 2.5 g of 1e in 60 mL of dry tetrahydrofuran over a period of 15 min. After stirring for 30 min a mixture of 34 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran was added fast. The cooling bath was removed, the reaction mixture was allowed to come to 0° C. and was poured into ice cold aqueous hydrochloric acid (60 mL, 0.5 N). The mixture was adjusted to pH 6, brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and concentrated under reduced pressure. Purification on silica gel (toluene/ethyl acetate: 3/1) gave 1.3 g of aldehyde 1f. 1H-NMR 200 MHz (CDCl3) δ: 7.12 (1H, d, J=7 Hz). 7.40-8.51 (9H, m), 9.26 (1H, d, J=8 Hz), 10.23 (1H, s).
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1)C)C.C([Li])CCC.CN(C)[CH:22]=[O:23]>CCOCC>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: CCOC(C)Oc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-(1-ethoxyethoxy)anisole was dissolved in ether (750 ml) and n-butyllithium (1.6M solution in hexanes; 500 ml) was added dropwise at ambient temperature under nitrogen. The mixture was stirred at ambient temperature for 2 hours, then it was cooled to 10° C. and a solution of dimethylformamide (94 g) in ether (150 ml) was added dropwise. The mixture was stirred at ambient temperature for 2 hours, then poured onto crushed ice. The product was extracted into ether, the combined extracts dried over magnesium sulphate, and the solvents removed in vacuo. The residual oil was dissolved in methanol (500 ml) and the stirred solution was cooled in ice and made strongly acidic by the addition of hydrochloric acid (2M). The resulting solid was collected by filtration, washed with water, dried in vacuo over phosphorus pentoxide and crystallised from petroleum ether (b.p. 60°-80° C.) to give 2-hydroxy-6-methoxybenzaldehyde as pale yellow needles (16 g), m.p. 69°-71° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([NH:11]C(=O)C)=[CH:9][N:8]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:25])[CH2:17][CH2:16]2)[CH:6]=1)(=O)[CH3:2].[OH-].[Na+]>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:7]3[N:8]=[CH:9][C:10]4[N:11]=[C:1]([CH3:2])[NH:4][C:5]=4[CH:6]=3)[CH2:20][CH2:19]2)=[CH:31][CH:30]=1
Reactant: CC(=O)Nc1cnc(N2CCN(CCCC(=O)c3ccc(F)cc3)CC2)cc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnc(N3CCN(CCCC(=O)c4ccc(F)cc4)CC3)cc2[nH]1
Temperature: 25 °C

Procedure:
5 g 4-[4-(4,5-Diacetylamino-2-pyridinyl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone and 25 g polyphosphoric acid are stirred and heated 1 hour at 140°. The reaction mixture is then cooled to room temperature, treated with 200 ml water, made alkaline with aqueous NaOH solution and extracted with methylene chloride. The extract is dried and evaporated. The residue is recrystallized from dichlormethane/diisopropylether to give the title compound, m.p. 180°-183°. M.p. of the bis-maleate 172°-173.5°.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:33][N:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:32][CH2:31]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(CCc2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 42.3 %

Procedure:
Intermediate A (180 mg, 1.11 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 133 mg, 3.33 mmol) in DMF (5 mL). The reaction was stirred for 20 min, then Intermediate 2b (310 mg, 1.11 mmol) was added in DMF (5 mL) and the resulting mixture heated to 60° C. for 3 h. After cooling, the reaction was quenched by dropwise addition of MeOH. The solution was loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 2-20% [2M NH3 in MeOH] in DCM, to give the title compound (200 mg, 0.47 mmol, 43%). LCMS (Method 4): Rt 0.28 min, m/z 407 [MH+].
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[CH3:41][N:42]1[C:46]([CH2:47][CH2:48]O)=[CH:45][CH:44]=[N:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:41][N:42]1[C:46]([CH2:47][CH2:48][O:38][C:35]2[CH:36]=[CH:37][C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:45][CH:44]=[N:43]1
Reactant: Cn1nccc1CCO
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIAD (7.78 mL, 39.53 mmol) was added dropwise to 4-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)phenol (12 g, 32.94 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (6.23 g, 49.41 mmol) and triphenylphosphine (12.96 g, 49.41 mmol) in THF (250 mL). The resulting solution was stirred at ambient temperature for 18 hours then split and added to a series of SCX columns (6). The crude product was eluted from the columns using 2M NH3/MeOH and the solvents evaporated. The crude product was diluted with DCM (200 mL) and washed with 2M NaOH (200 mL×2). The organic layer was dried over MgSO4, filtered and evaporated then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness giving a yellow solid, which was triturated with ether then dried to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine anhydrous Form A (9.18 g, 59.0%) as a cream solid.