Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(C1C(C2C=CC([C@H](NC(C3(N)COC3)=O)C)=C(F)C=2)=CC=CC=1Cl)=O.C(OC(=O)N[C@@H](C1C=CC(C2C=C(Cl)C=C(Cl)C=2OCC(F)F)=CC=1F)C)(C)(C)C.BrC1C=C(Cl)C=C(Cl)C=1OCC(F)F.ClC1C(OCC(F)F)=C(C2C=CC([C@H](N)C)=C(F)C=2)C=C(Cl)C=1.C1C2C(COC(=O)[NH:112][C:113]3([C:117](=[O:141])[NH:118][C@@H:119]([C:121]4[CH:126]=[CH:125][C:124]([C:127]5[CH:132]=[C:131]([Cl:133])[CH:130]=[C:129]([Cl:134])[C:128]=5[O:135][CH2:136][CH:137]([F:139])[F:138])=[CH:123][C:122]=4[F:140])[CH3:120])[CH2:116][O:115][CH2:114]3)C3C(=CC=CC=3)C=2C=CC=1>>[Cl:134][C:129]1[C:128]([O:135][CH2:136][CH:137]([F:138])[F:139])=[C:127]([C:124]2[CH:125]=[CH:126][C:121]([C@H:119]([NH:118][C:117]([C:113]3([NH2:112])[CH2:116][O:115][CH2:114]3)=[O:141])[CH3:120])=[C:122]([F:140])[CH:123]=2)[CH:132]=[C:131]([Cl:133])[CH:130]=1
Reactant: C[C@@H](NC(=O)C1(NC(=O)OCC2c3ccccc3-c3ccccc32)COC1)c1ccc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Agent: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Agent: C[C@@H](N)c1ccc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Agent: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F
Product: C[C@@H](NC(=O)C1(N)COC1)c1ccc(-c2cc(Cl)cc(Cl)c2OCC(F)F)cc1F

Procedure:
The title compound was prepared in analogy to intermediate 4 synthesizing {(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethyl}-carbamic acid tert-butyl ester in step A (using 1-bromo-3,5-dichloro-2-(2,2-difluoro-ethoxy)-benzene (intermediate 9) instead of methyl 2-bromo-6-chlorobenzoate), (R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylamine in step B and (3-{(R)-1-[3′,5′-dichloro-2′-(2,2-difluoro-ethoxy)-3-fluoro-biphenyl-4-yl]-ethylcarbamoyl}-oxetan-3-yl)-carbamic acid 9H-fluoren-9-ylmethyl ester in step C. Colorless oil. MS: 463.1; [M+H]+.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].C1(N2CCN([C:17](=[O:50])[C@@H:18]([NH:29]S(C3C=CC=C(N4CCCCC4=O)C=3OC(F)F)(=O)=O)[CH2:19][NH:20][C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[O:22])CC2)CC1.Cl>C(OCC)(=O)C>[ClH:28].[CH3:3][O:4][C:17](=[O:50])[C@@H:18]([NH2:29])[CH2:19][NH:20][C:21]([C:23]1[S:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[O:22]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)N1CCN(C2CC2)CC1)c1ccc(Cl)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CNC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
33 g (110.24 mmol) of intermediate 8 from step 22.4) were dissolved in 600 ml ethyl acetate and 250 ml HCl (2N in diethyl ether) was added. After 20 h stirring at RT the reaction was filtered and the solid dried under reduced pressure.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:29])([F:30])[F:31])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
The title compound, off-white solid, MS: m/e=435.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-4,6-bis-trifluoromethyl-benzoic acid (intermediate AN).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O>C1C=CC=CC=1.CN(C)C=O>[CH:8]([NH:12][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1])([CH3:9])[CH3:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3.5 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid and 3.4 ml of thionyl chloride in 20 ml of benzene is heated to reflux temperature for 3 hours together with 2 drops of dimethylformamide. The mixture is then evaporated to dryness and the residue is dissolved in 15 ml of dioxan. The solution is added dropwise at room temperature to a solution of 0.7 g of isopropylamine and 1.1 g of pyridine in 15 ml of dioxan and the reaction mixture is stirred at room temperature for 2.5 hours. Subsequently, the mixture is treated with 400 ml of water, extracted twice with 400 ml of ethyl acetate each time, the organic phases are washed twice with 200 ml of 1N hydrochloric acid each time, thereafter twice with 200 ml of saturated sodium chloride solution each time, and the combined organic phases are dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with ethyl acetate/n-hexane (1:2) as the eluent. In this manner there is obtained N-isopropyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide which can be recrystallized from ethyl acetate/n-hexane. M.p. 146°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[N:10](C1CCCCO1)[N:9]=[CH:8]2.Cl.C([O-])(O)=O.[Na+].CCOC(C)=O>CCO>[F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[NH:10][N:9]=[CH:8]2
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2-c2ccncc2)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2-c2ccncc2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 5-(2-fluoro-4-nitrophenoxy)-6-(pyridine-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.8 g, 6.45 mmol) in EtOH (30 mL) is added HCl (concentrated 5.0 mL). The mixture is stirred at 80° C. for 2 hours. Then aqueous NaHCO3 and EtOAc are added. The organic phase is dried over anhydrous MgSO4 and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (3:1) to give the desired product (1.95 g, 86.0% yield). MS (m/z): 351.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.OO.C(=O)([O-])[O-:24].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[C:18]([C:17]([NH2:16])=[O:24])=[N:20][CH:19]=[CH:15][CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ncccc1-c1c[nH]nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 4-(3-[4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0° C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl-2-pyridinecarboxamide as a white solid (67% yield), mp: 230-231° C. Anal. Calc'd for C15H11FN4O: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:25])=[O:5])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]=1)[CH2:10][C:9]2([CH3:25])[CH3:26])=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)Nc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A mixture of 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (706 mg, 2 mmol), aniline (0.22 mL, 2.4 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3 mmol) in dichloromethane (6 mL) and triethyl-amine (0.7 mL, 5 mmol). The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4,4-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (800 mg, 93%) as a brown oil which was used for next step without further purification: MS (ESI) M+1=429.2.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].Cl[C:32]1[C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([Cl:45])[CH:38]=2)[N:33]=1.C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C@H:9]([NH:8][C:32]3[C:41]([C:42]([OH:44])=[O:43])=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[C:37]([Cl:45])[CH:38]=4)[N:33]=3)[C:10]([OH:12])=[O:11])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 100 °C
Reaction time: 13 h
Yield: 41.3 %

Procedure:
A mixture of trifluoroacetic acid salt of (S)-2-amino-3-[4-(quinolin-4-yloxy)-phenyl]-propionic acid (0.296 g, 0.7 mmol), 2,6-dichloroquinoline-3-carboxylic acid (0.16 g, 0.66 mmol) and K2CO3 (0.46 g, 3.3 mmol) in dry DMSO (1 mL) is stirred for 13 h in a closed Pierce reaction vial at 100° C. temperature. After cooling the reaction mixture is diluted with water (25 mL), acidified with 2N aqueous HCl till pH 3, and the precipitated solid is collected on filter. The crude product is washed with water and recrystallized from DMF/EtOH (0.5 mL/0.5 mL) mixture to give the title compound as a yellow solid (0.14 g, 41%).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>ClCCl.[O-2].[O-2].[Mn+4]>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([CH:30]=[O:31])[CH:27]=[CH:26][C:25]=4[CH3:32])=[CH:22][CH:23]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(CO)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 96.4 %

Procedure:
5′-Hydroxymethyl-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (500 mg) in dichloromethane (30 ml) was treated with manganese dioxide (3 g) and the mixture stirred at 20 C for 18 h. The suspension was then filtered through celite and the mother liquor evaporated giving the title compound as a colourless oil (480 mg)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:23]([O:22][CH2:21][CH2:20][O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)C1
Reactant: BrCCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(OCCOCc2ccccc2)C1
Temperature: 80 °C
Yield: 22.2 %

Procedure:
A solution of 1.29 g of benzyl 3-hydroxypyrrolidine-1-carboxylate in 80 ml of THF is cooled to 0° C., 0.245 g of 60% NaH in oil is added and then 1.26 g of [(2-bromoethoxy)methyl]benzene and 0.108 g of tetrabutylammonium iodide and it is heated at 80° C. for 3 hours. 0.28 g of NaH and 0.40 g of [(2-bromoethoxy)methyl]benzene are added and it is heated at 80° C. for 2 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with 0.1M HCl solution, with a saturated solution of NaHCO3, it is dried and the solvent is evaporated under vacuum. The product thus obtained is purified by preparative HPLC and 0.46 g of the expected compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[Se:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[Se:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cnc(-c2ccc(Cl)cc2)[se]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc(-c2ccc(Cl)cc2)[se]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a suspension of 2-(4-chlorophenyl)selenazole-5-carbaldehyde (130 mg, 0.48 mmol) in methanol (5 ml) is added sodium borohydride (19 mg, 0.5 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 0.5 hour. The reaction mixture is quenched with saturated aqueous ammonium chloride solution (10 ml), and extracted with dichloromethane (3×25 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness to give [2-(4-chlorophenyl)selenazol-5-yl]methanol (127 mg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[Cl:21])=[C:10]([CH3:12])[CH:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23].C1(PC2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.CCOC(C)=O.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].O>[Cl:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[C:9]1[N:4]2[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([NH:27][CH:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:3]2=[CH:11][C:10]=1[CH3:12]
Reactant: COc1ccc(-c2c(C)cc3c(Br)cc(C)nn23)c(Cl)c1
Reactant: CCC(N)CC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)Nc1cc(C)nn2c(-c3ccc(OC)cc3Cl)c(C)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazine (0.99 g, 2.70 mmol), 1-ethylpropylamine (0.63 mL, 0.47 g, 5.40 mmol), 5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen4-yl](diphenyl)phosphine (0.26 g, 0.40 mmol), Cs2CO3 (1.38 g, 4.20 mmol) and Pd2(dba)3 (0.13 g, 0.14 mmol) in DME (15.0 mL) was refluxed for 17 h. After cooling to room temperature, the mixture was diluted with EtOAc. Water was added and the mixture was separated. The aqueous solution was extracted with EtOAc (2×) and the combined EtOAc solutions was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to dryness, the residue was subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to give 0.88 g (87%) of light yellow oil as the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J=8.5 Hz, 1H), 7.09 (d, J=2.6 Hz, 1H), 6.95 (dd, J=8.5, 2.6 Hz, 1H), 6.29 (s, 1H), 5.54 (s, 1H), 4.16 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.47–3.43 (m, 1H), 2.31 (s, 3H), 2.21 (s, 3H), 1.78–1.66 (m, 2H), 1.64–1.54 (m, 2H), 1.00 (t, J=7.3 Hz, 6H); MS m/z 372.24 (M++H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[N:16]1([C:14](=[O:15])[CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:22])[C:4]([OH:23])=[O:3])=[CH:11][CH:10]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
4-[2-(4-Morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.4 g) in methanol (70 mL) was treated with sodium carbonate (0.158 g) in water (2 mL), and the mixture was stirred at room temperature for 1.5 hours. After the solvents were removed in vacuo, dichloromethane (40 mL) and water (40 mL) were added and the mixture was acidified with 3N hydrochloric acid. Tetrahydrofuran was added to dissolve the solids, then the separated aqueous layer was extracted twice with dichloromethane-tetrahydrofuran (1:1). The combined organic layers were dried (MgSO4), evaporated, and the residual solid was crystallized from dichloromethane-tetrahydrofuran-hexane to yield 0.36 g of 4-[2-(4-morpholinyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 182°-184° C.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH:2]=[C:3]([CH3:5])[CH3:4].[NH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH2:29][CH3:30]>>[CH2:29]([N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][NH:22][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:7]([O:6][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])[CH:8]=1)[CH3:30]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCOc1ccc(C(=O)O)cc1OCC=C(C)C
Product: CCN1CCCC1CNC(=O)c1ccc(OCC=C(C)C)c(OCC=C(C)C)c1
Yield: 55 %

Procedure:
In a manner identical to Example 15, 3,4-diprenyloxybenzoic acid (1.45 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.09 g (55%) of the aimed compound. m.p. 80.0-81.5° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C1N2CN3CN(C2)C[N:12]1C3.Cl>C(Cl)(Cl)Cl>[NH2:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Product: NCC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 106.9 %

Procedure:
2-Bromoacetophenone (18 g, 90 mmol) was dissolved in 900 ml of chloroform. Hexamethylenetetraamine (13.87 g, 99 mmol) was added thereto and the reaction mixture was stirred at 60° C. for 4 hours. After stirring, the reaction mixture was cooled down to room temperature, filtered, and the collected precipitate was suspended in 180 ml of ethanol. To the suspension thus obtained was added dropwise 90 ml of conc. HCl, and the reaction mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was filtered to remove a white precipitate, the filtrate was concentrated under reduced pressure to obtain a yellow solid. This solid was recrystallized from a mixture of methanol and ethyl acetate (1:50, v/v) to obtain 13 g of 2-aminoacetophenone as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[C:26]=1[OH:33]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:26]4[C:25]([F:24])=[CH:30][C:29]([F:31])=[CH:28][C:27]=4[F:32])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(F)cc(F)cc4F)ncnc32)CC1

Procedure:
4-[4-(2,4,6-Trifluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2,4,6-trifluorophenol (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.99-2.05 (m, 4H), 2.97-3.05 (m, 2H), 4.07-4.11 (m, 2H), 5.00-5.05 (m, 1H), 7.51-7.55 (m, 2H), 8.53 (s, 1H), 8.60 (s, 1H). Mass spectrum MH+=450.
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]([CH3:13])=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.C(O)=O>O>[C:10]([O:9][CH2:8]/[CH:7]=[C:6](\[CH3:13])/[CH:5]=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: CC(=O)OC/C=C(\C)C=O
Reaction time: 3 h
Yield: 75.6 %

Procedure:
48.8 parts of 1,1,4-triacetoxy-2-methyl-but-2-ene, having the isomer composition stated in Example 1, 400 parts of formic acid and 10.8 parts of water are boiled for 3 hours. After stripping off the formic acid and water on a rotary evaporator, fractional distillation of the residue gives 21.5 parts of 4-acetoxy-2-methylcrotonaldehyde (75.6% of theory) of boiling point 102°-105° C./21 mbar (nD20 =1.4642). According to NMR analysis, the aldehyde obtained consists of 98.3% (E)- and 1.7% (Z)-4-acetoxy-2-methylcrotonaldehyde.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and methoxy-acetyl chloride the title compound is obtained as colorless solid.