Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[C:4]([F:32])[CH:3]=1.[CH3:33][N:34]([CH3:38])[C:35]([NH2:37])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Br:1][C:2]1[CH:3]=[C:4]([F:32])[C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:6][C:7]=1[C:8]1[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:37][C:35](=[O:36])[N:34]([CH3:38])[CH3:33])[CH:12]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(Cl)cc21
Reactant: CN(C)C(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NC(=O)N(C)C)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A suspension of 1-(4-bromo-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (0.360 g, 0.698 mmol), N,N-dimethylurea (0.307 g, 3.49 mmol) and Cs2CO3 (0.682 g, 2.094 mmol) in dioxane (8 mL) was sparged with Ar, treated with XantPhos (0.121 g, 0.209 mmol) and Pd2(dba)3 (0.096 g, 0.105 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, the solids removed via filtration and rinsed with EtOAc. The filtrate was treated with brine, filtered again to remove solids and the layers separated. The organic layer was washed a second time with brine, dried over MgSO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and stirred for 1 h. The resulting solid was collected via filtration and dried to afford 3-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-1,1-dimethylurea (37 mg, 9% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 9.10 (s, 1H), 8.72 (s, 1H), 8.65 (s, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.69 (d, J=10.8 Hz, 1H), 7.42 (m, 2H), 7.26 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 2.97 (s, 6H), 1.24 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 567.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][C:28]1[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>C(N(CC)CC)C>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[C:34]([CH3:35])[C:28]=4[CH3:27])=[O:23])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1cccc(N)c1C
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)c2ccc(C(=O)N3Cc4ccccc4Cc4ccccc43)cc2)c1C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
As described for Example 123, a mixture of 0.361 g of 4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]benzoyl chloride, 0.101 g of triethylamine and 0.145 g of 2,3-dimethylaniline is stirred for 1.5 hr. and worked up to give 0.44 g of crystals, m.p. 248°-251° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[CH2:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23].OS(O)(=O)=O.[N:30]([O-])=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:13]=[N:30][CH:11]=[C:10]2[CH3:12])=[O:24]
Reactant: C=C(C)c1cc(C(=O)OC)c(Nc2ccc(Cl)cc2Cl)c(F)c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2c(C)cnnc2c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.4 %

Procedure:
To a solution of 4-amino-2-(2,4-dichlorophenylamino)-3-fluoro-5-isopropenyl-benzoic acid methyl ester (89.9 mg, 0.243 mmol) in THF (2 mL) and conc. H2SO4 (0.050 mL, 0.94 mmol) was added a solution of NaNO2 (24.0 mg, 0.348 mmol) in water (0.5 mL) at 0° C. The reaction temperature was kept below 5° C. during the addition. The reaction mixture was warmed to room temperature, and 2 mL of water was added. After stirring in the dark for 4 days, the reaction mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (54 mg, 58%).
Reaction SMILES: Br.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32]Cl)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:35][CH3:36])=[C:25]([NH:28][C:29](=[O:34])[CH:30]=[CH:31][CH2:32][N:6]4[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: FC1CCNCC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCCl
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(F)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
131 mg of 4-Fluoro-piperidine hydrobromide was added to 300 mg of 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 0.37 ml of DIEA were dissolved in 5 ml THF stirred at 70° C. overnight. The mixture was then diluted with ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4% methanol in chloroform to give 189.4 mg of 4-(4-Fluoro-piperidin-1-yl)-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:17](=[O:33])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.BrC[C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:25][C:22]1[CH:21]=[C:20]2[C:19](=[CH:24][CH:23]=1)[N:18]([CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[C:17](=[O:33])[CH:16]=[C:15]2[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH2:13][CH2:12]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(=O)n(Cc3ccncc3)c3ccc(Cl)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(Cl)ccc2n1Cc1ccncc1
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
4-(6-Chloro-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydroquinolin-4-ylamino)-piperidine-1-carboxylic acid t-butyl ester (0.58 g, 1.2 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes before evaporating under reduced pressure. The crude amine was dissolved in acetonitrile (25 mL) prior to addition of sodium carbonate (1.22 g) and a drop of triethylamine. The mixture was stirred for 5 minutes before addition of 2-(bromomethyl)naphthalene (0.31 g, 1.4 mmol). After 2 hours the reaction was found to be complete by TLC analysis and the mixture was diluted with ethyl acetate, washed with 1N NaOH, and dried with sodium sulfate. Evaporation under reduced pressure gave the crude product which was purified by silica chromatography using DCM and methanol eluent to give the title compound (0.42 g). 1H NMR (300 MHz, CDCl3) δ ppm 2.04 (2H, m), 2.22 (2H, m), 2.67 (2H, m), 3.23 (2H, m), 3.67 (1H, m), 4.02 (2H, s), 5.20 (1H, m), 5.47 (2H, m), 5.82 (1H, s), 6.93 (1H, d, J=8.96 Hz), 7.05 (2H, m), 7.32 (1H, m), 7.46-7.52 (2H, m), 7.65 (1H, m), 7.72 (1H, m), 7.84 (3H, m), 7.91 (1H, m), 8.48 (2H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][C:32]([CH3:37])([CH3:36])[CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][C:32]([CH3:36])([CH3:37])[CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: CC1(C)CC(CCCBr)CCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 223 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)-2,2-dimethyltetrahydro-2H-pyran.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:13]=[CH:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[CH:21]1OCCO1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>Br>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[CH2:2]([N:9]1[C:10]2[N+:11](=[CH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]=2)[CH:12]=[CH:13]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Cn2cc[n+](Cc3ccccc3)c2C2OCCO2)cc1
Agent: Br
Agent: [Br-]
Agent: [Na+]
Product: c1ccc(Cn2cc[n+]3cc4ccccc4cc23)cc1
Reaction time: 48 h

Procedure:
A mixture of 1-benzyl-2-(1,3-dioxolan-2-yl)-3-benzyl-imidazolium bromide (17.3 g) and 450 ml of 48% HBr was heated on an oil-bath (120°-130° C.) and stirred for 48 h. The mixture was concentrated in vacuo at 60° C. and the resulting green colored residue was redissolved in water. The aqueous solution was treated with a sodium perchlorate (2 equiv) solution and the precipitated product was separated by decanting, and crystallized from CH3CN-EtOAC. The solid product was collected by filtration, washed with ethanol and dried in vacuo to afford 18.6 g of 1-benzylimidazo[1,2-b]isoquinolin-4-ium perchlorate (Formula II: A=1-benzylimidazole; R1 =R6 =H; X- =ClO4-).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14](Cl)=[O:15].C(N(CC)CC)C>O1CCOCC1.O.C(OC(=O)C)C>[CH3:12][N:13]([S:17][C:18]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])[CH3:19])[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(SC(C)(C)C(=O)c1ccccc1)C(=O)ON=C1SC(C)(C)C(=O)N1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2.5 g (0.015 m) of 3,5,5-trimethyl-2-oximino-thiazolidin-4-one and 3.93 g (0.015 m) of N-methyl-N-(2-benzoyl-2-propanesulfenyl)carbamoyl chloride in 100 ml of dioxane was added 1.5 g (0.015 m) of triethylamine. After stirring at room temperature for 16 hours, the reaction mixture was diluted with water and the product isolated in ethylacetate. Recrystallized from isopropyl ether. Weight of the procut 1.3 g, m.p. 98°-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Li])(C)(C)C.[CH:19](N1CCOCC1)=[O:20]>C1COCC1.CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]=[O:20])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=CN1CCOCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1ccc(Br)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-bromo-2-(trifluoro-methoxy)iodobenzene (9.93 g, 28 mmol) in THF (150 mL) at -78° C. was added tert-butyllithium (37 mL of a 1.5 M solution in pentane, 56 mmol) dropwise over a period of 20 min. The pale yellow solution was stirred at -78° C. for 1.5 h when N-formylmorpholine (6.5 mL; 58 mmol) was added. The resulting solution was stirred at -78° C. for 15 min and the cooling bath was removed. The mixture was stirred for an additional 1 h, when 0.25 M aqueous citric acid (100 mL) was added. The mixture was diluted with EtOAc (150 mL), the layers were separated, the organic phase was washed with brine (100 mL), dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified using pressurized silica gel column chromatography eluting with hexane to give 4-bromo-2-(trifluoro-methoxy)benzaldehyde as a colorless liquid (TLC Rf =0.45 (hexanes)).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.Cl.C[O:32][C:33](=[O:36])[CH2:34][NH2:35].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C.Cl.N1C=CC=CC=1.C1COCC1>[C:33]([CH2:34][NH:35][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([OH:36])=[O:32]
Reactant: O=C(O)C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: O=C(O)CNC(=O)C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a stirred solution in CH2Cl2 (0.5 mL), THF (20 mL), and pyridine (20 mL) of 2,2-bis(4-hydroxyphenyl)acetic acid (0.94 g, 3.85 mmol), prepared as in Example 31, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.10 g, 5.76 mmol), glycine methyl ester hydrochloride (0.723 g, 5.76 mmol), and N-methylmorpholine (0.63 mL, 5,76 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate and aqueous 0.5 N HCl. The organic layer was washed with 0.5 N HCl (3X), saturated aqueous NaHCO3 (3X), and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dried to constant weight on high vacuum to give 1.05 g (87%) of 2,2-bis(4-hydroxyphenyl)acetic acid-N-carboxymethyl amide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([CH3:22])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:36])[CH3:22]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(N)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Temperature: 140 °C

Procedure:
1-{[6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone (500 mg, 1.21 mmol), ammonium acetate (934 mg, 12.11) and cyanoborohydride on polymer support (1.82 g, 3.63 mmol) were mixed in methanol (3 ml) and heated in micro at 140° C. for 10 min. The mixture was concentrated and treated with NaHCO3 and DCM. The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/heptane followed by EtOAc/methanol). The diasteromers were separated on preparative HPLC (Kromasil column, water buffered with 2 g NH4OAc/l, pH set to 5.5 with HOAc, and MeCN, 25%-75%) to give the syn-isomer (1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (98a-rac-1) as first eluted isomer (assignment by 1H-NMR).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=Cc1c(O)ccc2c1CCCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(NCc2c(O)ccc3c2CCCO3)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5- carboxaldehyde (308 mg, 1.73 mmol) and p-aminoacetophenone (236 mg, 1.73 mmol) in methanol (8 mL) was heated at reflux for one hour. The mixture was cooled to 15° at which time the intermediate Schiff's base crystallized. After filtration and drying a light orange product (221 mg, 43.3%) was obtained. This material was suspended in methanol (8 mL) and sodium borohydride (28 mg, 0.74 mmol) was added. After stirring at room temperature for ten minutes the mixture was poured into water (75 mL) and the resulting suspension neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(4-acetylphenyl) aminomethyl-3,4-dihydrobenzopyran (170 mg, 76.6%), m.p. 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:3]3[C:2]([Cl:1])=[C:10]4[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]4=[O:11])=[CH:4]3)=[CH:21][CH:22]=2)[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Reactant: BrCc1ccc(-n2cncn2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-n4cncn4)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A suspension of 5-chloro-1-isobutyl-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (103 mg, 0.4 mmol), 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole (93 mg, 0.48 mmol) and cesium carbonate (195 mg, 0.6 mmol) in anhydrous DMF (3 mL) is stirred at room temperature for 3 hours. The mixture is diluted with 20 mL of saturated sodium bicarbonate, and then extracted with CH2Cl2 three times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration through celite, the filtrate is concentrated to dryness under vacuum to give 160 mg of crude product as light brown solids, which is used in the next step without further purification. MS (ESI) m/z 413.2 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@H:4]([OH:8])[C@@H:5]([OH:7])[CH3:6].Cl[C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.Cl>C1(C)C=CC=CC=1.COCCOC.O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:7][CH:5]([CH3:6])[CH:4]([OH:8])[CH3:3])=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: C[C@H](O)[C@@H](C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OC(C)C(C)O)c23)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
Add 4.8 ml of 12.5 N sodium hydroxide solution to a mixture of 2.68 g (29.70 mmol) (2R,3S)-butane-2,3-diol in 45 ml toluene, 15 ml 1,2-dimethoxyethane and 15 ml water at 70° C. After adding 0.20 g (0.60 mmol) tetra-n-butylammonium hydrogensulphate and 2.00 g (5.94 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, stir the reaction mixture for 17 h at 70° C. After cooling to room temperature, adjust to pH 7 with concentrated hydrochloric acid. Extract three times with 100 ml dichloromethane each time. Wash the combined organic extracts with satd. sodium chloride solution, dry over sodium sulphate, filter, and concentrate by vacuum evaporation. Purify the raw product by preparative RP-HPLC (gradient: water/acetonitrile). 1.26 g (54% of theor.) of the desired product is obtained as (R,S/S,R) racemate.
Reaction SMILES: Br.[NH2:2][C@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@H:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][C@H:28]([NH:43]C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)[C:29](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:30])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:10]=[C:9]1[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][C@@H:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:3]1[NH:2][C:29](=[O:30])[C@H:28]([CH2:27][C:24]1[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=1)[NH2:43]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Agent: Br
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (2S,3S)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (91 mg) in 10 mL of THF was added Fmoc-Phe-Opfp (185 mg) followed by DIEA (58 μL). The reaction mixture was stirred for 30 min and treated with DBU (0.1 mL) and stirred for 10 min. The material thus produced was used in the next step without purification or characterization.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13](=O)[C:14]([O:16]CC)=O.[CH3:20]/[C:21](/[NH2:24])=[N:22]/[NH2:23].Cl>CCO>[CH3:20][C:21]1[NH:24][C:14](=[O:16])[C:13]([CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[N:23][N:22]=1
Reactant: C/C(N)=N/N
Reactant: CCOC(=O)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: Cc1nnc(CN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of ethyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-oxopropanoate [J. Org. Chem., (1985), 50 (1), 91] (4.29 g, 16.4 mmol), acetamidrazone hydrochloride (1.80 g, 16.4 mmol) in anhydrous EtOH (85.8 mL) was heated to 80° C. for 3 h then cooled to rt and stirred for an additional 16 h. The reaction mixture was filtered through a flitted funnel resulting in 3.28 g, (73% yield) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H), 4.73 (s, 2H) and 7.74-8.12 (m, 4H); MS (ES+): m/z 271.08 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Product: CN1CCN(c2cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c2)CC1

Procedure:
was prepared according to Scheme C1 (step A) from (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (200 mg, 0.59 mmol), 1-methylpiperazine (71 mg, 0.71 mmol), caesium carbonate (269 mg, 0.83 mmol), palladium (II) acetate (6.6 mg, 0.03 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.04 mmol). MS (LC-MS): 358.0 [M]+; tR (HPLC conditions c): 3.98 min.