Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH:20]=O.[CH2:26]=[C:27]([CH3:29])[CH3:28].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[CH:12]1([NH:11][S:8]([C:5]2[CH:6]=[C:7]3[C:2](=[CH:3][CH:4]=2)[NH:1][CH:20]([C:19]2[CH:22]=[C:23]([F:25])[CH:24]=[C:17]([Br:16])[CH:18]=2)[CH2:26][C:27]3([CH3:29])[CH3:28])(=[O:10])=[O:9])[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: Nc1ccc(S(=O)(=O)NC2CCC2)cc1
Reactant: C=C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To a stirred solution of 4-amino-N-cyclobutyl-benzenesulfonamide (2.8 g, 12.4 mmol) and 3-bromo-5-fluoro-benzaldehyde (2.7 g, 13.6 mmol) in acetonitrile (150 mL) were added isobutene (2.7 mL, 37.2 mmoll) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.54 g, 2.5 mmol). The resulting mixture was stirred at 80° C. for 18 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (2.3 g, 40%) as a light yellow solid: MS (ESI) M+1=467.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([CH:19]=O)=[CH:14][CH:13]=3)=[N:2]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:19][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]([C:3]2[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=2)=[CH:18]3)[CH2:24][CH2:23]1
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]c4ccccc34)cc2c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc3[nH]c(-c4n[nH]c5ccccc45)cc3c2)CC1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A mixture of the aldehyde (6-3, 50 mg, 0.19 mmol), N-methylpiperazine (191 mg, 1.91 mmol), acetic acid (0.06 mL) and sodium triacetoxyborohydride (406 mg, 1.91 mmol) in N,N-dimethyl formamide (3 mL) was stirred at the ambient temperature for 11 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Chromatography (SiO2, 30% methanol in ethyl acetate) afforded the desired product (6-4) as a light tan solid; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 11.56 (s, 1H), 8.23 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.49 (t, 1H, J=7.6 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.31 (t, 1H, J=7.6 Hz), 7.12–7.11 (m, 2H), 3.57 (s, 2H), 2.52–2.26 (m, 8H), 2.21 (s, 3H).
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13].CC(N=NC(C#N)(C)C)(C#N)C>CC(N=NC(C#N)(C)C)(C#N)C.C(O)C>[CH3:11][CH:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][PH:2](=[O:4])[OH:3]
Reactant: O=[PH2][O-]
Reactant: C=C(C)CC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C[PH](=O)O)CC(C)(C)C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A 2 L 4-neck flask, equipped with thermocouple well, a dropping funnel, overhead stirrer and reflux condenser is charged with 199 grams (1.88 moles) of sodium hypophosphite monohydrate and 500 mL of 2B ethanol. Into the resultant stirred suspension is added via the dropping funnel, 52 mL (1.87 moles) of concentrated sulfuric acid. During the addition the reaction mixture temperature rises from 21° C. to 27° C. After approximately 15 minutes, 100 mL (0.624 moles) of 2,4,4-trimethyl-1-pentene is added, followed by 10.24 g (0.062 moles) of AIBN powder. The reaction mixture is heated at reflux under a nitrogen atmosphere for 20 hours. An additional 6.84 g (0.042 moles) of AIBN powder is added and the mixture is refluxed under nitrogen for another 20 hours. Solvent is removed under vacuum and the residue is partitioned between 400 mL heptane and 1 L of water. The heptane layer is concentrated under vacuum to give 98 grams (88% of theory) of 2,4,4-trimethylpentyl phosphinic acid as a colorless oil.
Reaction SMILES: [Br:1]Br.[CH:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([O:15][C:16](=[O:17])[C:9]3=[CH:8][CH:7]=[CH:6]2)=[O:14])[CH:12]=1>[N+]([O-])(O)=O>[CH:3]1[CH:12]=[C:11]2[C:13]([O:15][C:16](=[O:17])[C:9]3=[C:10]2[C:5](=[CH:6][C:7]([Br:1])=[CH:8]3)[CH:4]=1)=[O:14]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: BrBr
Solvent: O=[N+]([O-])O
Product: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Temperature: 70 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
Bromine (13.2 mL, 256 mmol) was added to a stirred solution of 1,8-naphthalic anhydride (50 g, 252 mmol) in 70% nitric acid (1000 mL) at 25° C. over a period of 10 min. The resulting brown solution was stirred at 70° C. for 2 hrs and cooled overnight. The cream colored precipitate was collected by filtration and washed with water (4×150 mL). The isolated product was dried in vacuum for 24 hrs, resulting in off-white crystalline solid (12.0 g, 20% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C(N(CC)CC)C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.[Cu]Br>[CH3:20][C:19]([CH3:22])([C:18](=[O:23])[C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#CCOc1ccccc1
Agent: [Cu]Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C#CCOc1ccccc1
Temperature: 80 °C
Yield: 74 %

Procedure:
13.2 g (0.1 mol) of phenyl propargyl ether are added dropwise to a mixture of 10.1 g (0.1 mol) of triethylamine and 1.43 g of copper-(I) bromide in 60 ml of toluene at 20° C., under a nitrogen atmosphere and with stirring. The mixture is subsequently stirred at 20° C. for 30 minutes. Thereafter, 12 g (0.1 mol) of pivaloyl chloride are added dropwise in the course of 15 minutes. The reaction mixture is heated to 80° C. and is stirred at this temperature for 10 hours. After cooling to room temperature, the reaction mixture is washed first with dilute aqueous hydrochloric acid and then with water. The organic phase is concentrated by stripping off the solvent and the residue which remains is distilled under a high vacuum. 16 g (75% of theory) of 2,2-dimethyl-6-phenoxyhex-4-in-3-one are obtained in this manner in the form of a liquid.
Reaction SMILES: ClC(OC(Cl)C)=O.C([N:15]1[CH2:24][CH2:23][C:22]2[C:21]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[N:20][C:19]([S:36][CH3:37])=[N:18][C:17]=2[CH2:16]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>ClCCCl>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:21]2[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]=3[N:18]=[C:19]([S:36][CH3:37])[N:20]=2)=[CH:27][CH:28]=1
Reactant: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
1-Chloroethyl chloroformate (572 mg, 4 mmol) was added dropwise to a mixture of 7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (860 mg, 2 mmol) and diisopropylethyl amine (516 mg, 4 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated with diethyl ether to yield the product as a beige solid (454 mg).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH:19]=[CH:20][CH:21]=1>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][C:24]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:25])[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C(Cl)CCc1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Yield: 50.9 %

Procedure:
To a solution of (Z)-methyl 3-aminobut-2-enoate (1.70 g, 14.8 mmol) and pyridine (1.30 g, 16.4 mmol) in DCM (25 mL) was added a solution of 3-(3-fluorophenyl)propanoyl chloride (2.77 g, 14.8 mmol) in DCM (5 mL) dropwise with stirring. At the end of addition, the mixture was stirred further at rt for 1 h. It was then washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a white solid (2.00 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[K+].[Br-]>C(O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)NCCN)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NCCNC2(c3ccc(Cl)cc3)OC(=O)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a flask equipped with a Dean-Stark water separator is charged 500 ml. of toluene, 24.0 g. (0.10 mole) of 2-(p-chlorobenzoyl) benzoic acid and 21.4 g. (0.10 mole) of N-(2-aminoethyl)-4-methylbenzene sulfonamide. The mixture is stirred and refluxed until the water level in the separator is constant. The reaction is then allowed to cool to room temperature and the resultant solid is filtered off, washed with 100 ml. of toluene and dried to give the above named phalide; m.p. 177°-179°C.: infrared (KBr), peaks at 3.00, 3.09, 3.37, 3.42, 3.48, 5.76, 6.25, 6.71, 7.42, 7.72, 8.58, 9.12, 9.90, 11.45, 12.80, 13.70, 17.30 and 18.20μ; ultraviolet (95% ethanol) maximum at 226 mμ (E 1cm 1% 637), 257 mμ (shoulder); N.M.R. (pyridine- d6) δ 2.22 (CH3), 3.57(4H, NCH2CH2N unresolved multiplet). Analysis: Calculated for C23H21ClN2O4S: C 60.4; H 4.6; N 6.1; Cl 7.8; S 7.0; Found: C 60.2; H 4.9; N 6.1; Cl 7.7; S 7.7.
Reaction SMILES: COC1C=C(C=CC=1OC)C(C1C=CC=C(N)C=1)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=1)=[O:26]>[Pd].C(OCC)(=O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1)=[O:26]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Agent: COc1ccc(C(=O)c2cccc(N)c2)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc(N)cc2)cc1OC

Procedure:
3,4-Dimethoxy-4'-aminobenzophenone was prepared analogously to 3,4-dimethoxy-3'-aminobenzophenone using 3,4-dimethoxy-4'-nitrobenzophenone (1 g, 3.5 mmol) and 0.1 g of 10% palladium on carbon catalyst in 110 mL of ethyl acetate. The crude product was purified by flash column chromatography (silica gel, 12% ethyl acetate/methylene chloride) to afford 0.32 g (36%) of the product as a yellow solid: mp 189-191° C.; 1H NMR (CDCl3) δ 7.80-7.62 (m, 2 H); 7.45-7.29 (m, 2 H), 6.96-6.80 (m, 1 H), 6.75-6.61 (m, 2 H), 4.14 (s, 2 H), 3.95 (s, 3 H), 3.93 (s, 3 H); 13C NMR (CDCl3) δ 194.2, 152.2, 150.5, 148.8, 132.6, 131.3, 128.0, 124.3, 113.6, 112.3, 109.7, 56.0; Anal. Calcd for C15H15NO3. Theoretical: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.95; H, 6.18; N, 5.13.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[S:21]1[C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=[N:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:26]([C:25]3[S:21][N:22]=[CH:23][CH:24]=3)=[O:27])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccns1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccns1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-isothiazolecarboxylic acid as starting materials, MS (LC/MS): 414.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][NH:20][C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:27]([C:16]1([C:6]2[C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:25][CH2:24][C:23]2[N:22]=[CH:21][N:20]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19](=[O:26])[C:18]=2[CH2:17]1)#[N:28]
Reactant: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc2c(c1=O)CC(C#N)(c1ccc(OC)c3oc4ccccc4c13)CC2

Procedure:
To a solution of the compound obtained in example 13 (170 mg, 0.46 mmol) in 5 ml of dry DMF was added ethyl bromoacetate (84.5 mg, 0.5 mmol) and cesium carbonate (195.6 mg, 0.6 mmol) at room temperature for 1 hr. Once the reaction has completed, the reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, followed by brine, and concentrated under vacuum. The crude product was purified by column chromatography to get 175 mg (83.2% yields) of the product. MP-106.2-125.1° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:42])([F:43])[F:41])[CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(NC(=O)c2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Benzoyl chloride (66 μL, 0.5 M in anhydrous DCM, 0.03 mmol, 1.1 equiv.) was added to a solution of TFA salt of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (15 mg, 0.03 mmol, 1.0 equiv.) and triethylamine (16 μL, 0.09 mmol, 3.0 equiv.) in anhydrous DCM (1 mL). The resulting mixture was stirred at rt for 3 h. Purification by pre-HPLC gave the title compound in 83% yield. Mass: M+H+: 500.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[Cl:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([O:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][N:19]=[C:18]3[NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)=[N:3][CH:4]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Fc1cc(Cl)cnc1Cl
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(Cl)cc4F)cc23)n1

Procedure:
The compound of Example 154 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,5-dichloro-3-fluoropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:25]3[N:26]([CH:33]=[C:34]([C:36]([OH:38])=O)[CH:35]=3)[N:27]=[CH:28][C:29]=2[C:30](=[O:32])[NH2:31])[C:19]([CH3:40])([CH3:39])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].F[P-](F)(F)(F)(F)F.[N:48]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=[N:49]1.NN>CN(C)C=O.O>[C:30]([C:29]1[CH:28]=[N:27][N:26]2[CH:33]=[C:34]([C:36]([NH:48][NH2:49])=[O:38])[CH:35]=[C:25]2[C:24]=1[NH:23][C@@H:20]1[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:18][C:19]1([CH3:39])[CH3:40])(=[O:32])[NH2:31]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)O)cc23)C(C)(C)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(C(=O)NN)cc23)C(C)(C)C1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Hunig's base (0.752 mL, 4.30 mmol) was added to a mixture of (R)-4-((1-(tert-butoxycarbonyl)-3,3-dimethylpiperidin-4-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (619 mg, 1.435 mmol) and BOP (952 mg, 2.152 mmol) in N,N-dimethylformamide (4 mL). After 1 h at room temperature, hydrazine (0.225 mL, 7.17 mmol) was added. After additional 17 h at room temperature, the mixture was diluted with water to give a suspension. The precipitate was collected by filtration to give (R)-tert-butyl 4-((3-carbamoyl-6-(hydrazinecarbonyl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (0.4863 g, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.08 (d, J=9.2 Hz, 1H), 9.64 (s, 1H), 8.27 (s, 1H), 8.03 (d, J=1.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 4.13-4.00 (m, 1H), 3.87 (br. s., 1H), 3.60 (d, J=13.2 Hz, 1H), 3.17 (d, J=7.9 Hz, 1H), 2.92 (br. s., 1H), 1.90 (dd, J=13.4, 3.5 Hz, 1H), 1.62-1.48 (m, 1H), 1.46-1.35 (m, 9H), 0.98 (s, 3H), 0.92 (s, 3H); LC retention time: 3.295 min (analytical HPLC Method H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH:17](O)[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)c2ccccc2CC1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Br)cccc1-n1ccc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Step 3 A solution of crude 2-(3-bromo-2-methylphenyl)-3-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (600 mg, 1.806 mmol) in DCM (30 mL) was treated with triethylsilane (15 mL, 94 mmol) and the resulting mixture was treated slowly with TFA (1.392 mL, 18.06 mmol). The mixture was stirred at rt for 2 h, then was concentrated and the residue was dissolved in DCM. The solution was washed with NaHCO3 (aq) and water, then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 to 60:40 hexane-EtOAc) to give 2-(3-bromo-2-methylphenyl)isoquinolin-1(2H)-one as a white solid (380 mg, 67%). Mass spectrum m/z 314, 316 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:20][C:17]1[CH:18]=[C:19]2[C:14]([N:13]=[CH:12][C:11](=[O:21])[N:10]2[CH2:9][CH2:8][N:5]2[CH2:4][CH2:3][CH:2]([NH:1][CH2:33][C:31]3[CH:30]=[CH:29][C:26]4[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=4[N:32]=3)[CH2:7][CH2:6]2)=[CH:15][CH:16]=1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1CSc2ccc(CNC3CCN(CCn4c(=O)cnc5ccc(F)cc54)CC3)nc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To 10 mL of a chloroform solution containing 183 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 114 mg of 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, 36 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 228 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=100:1] to give 135 mg of 7-fluoro-1-(2-(4-((3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methylamino)piperidin-1-yl)ethyl)quinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[OH:9]O.[C:11](O)(=[O:13])C>>[CH3:8][C:3]1[CH:2]=[N+:1]([O-:9])[CH:6]=[C:5]([CH3:7])[C:4]=1[O:13][CH3:11]
Reactant: Cc1cncc(C)c1
Reactant: OO
Reactant: CC(=O)O
Product: COc1c(C)c[n+]([O-])cc1C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3,5-lutidine (15 kg, 140.2 moles) was dissolved in acetic acid (48 l) at 60° C. Hydrogen peroxide (8430 ml, 98 moles) was added during 3 hours. The solution was heated to 90° C. and kept at this temperature for 3 hours. The reaction mixture was cooled to 60° C. and hydrogen peroxide (3500 ml, 41 moles) was added during 1 hour. The temperature was raised to 90° C. and kept there for 16 hours. The reaction mixture was evaporated at reduced pressure (70° C. 300 mm Hg). The residue (approx 25 liters) was cooled and pH adjusted to 10 with NaOH-solution (23 liters 10M). Acetonitrile (30 liters) was added and the mixture was stirred for 30 minutes. The sodiumacetate was separated off and washed with 10 l acetonitrile. The liquid phase was evaporated at reduced pressure (55° C., 200 mm Hg). The remaining solution (approx 25 liters) was extracted with CH2Cl2 (20 liters and 3×5 liters). The combined organic layers were dried over MgSO4, filtrated and evaporated at reduced pressure (50° C. 200 mm Hg). When all CH2Cl2 had distilled off unreacted 3,5-lutidine was evaporated at 75° C., 8 mm Hg. Yield 14940 g of 3,5-dimethylpyridine-N-oxide. The identity was confirmed with 1 H and 13C NMR.