Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)=[O:26])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:36][C:37]1[C:42]([C:43]#[N:44])=[C:41](Cl)[N:40]=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:36][C:37]1[C:42]([C:43]#[N:44])=[C:41]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]4)=[O:26])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:40]=[CH:39][N:38]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC(C)N1CCN(C(=O)CCCC#Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)CC1
Temperature: 120 °C
Reaction time: 48 h
Yield: 22.5 %

Procedure:
To a solution of (S)-2-(1-aminoethyl)-5-(6-(4-isopropylpiperazin-1-yl)-6-oxohex-1-yn-1-yl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, purity 10%, 0.03 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (6 mg, 0.04 mmol) in tert-butanol (3 ml) was added DIEA (44 μl, 0.25 mmol) and the reaction mixture was stirred at 120° C. for 2 days. The solvent was removed under reduced pressure. Ethyl acetate was added and the organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 100% hexane/AcOEt, 0-8% AcOEt/MeOH) to give 4 mg (25% yield) of the title compound as a white solid. Purity 96%.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9](F)[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[F:14][C:7]1[C:8]([F:13])=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[C:4]([C:18]1[S:17][C:16]([Br:15])=[CH:20][CH:19]=1)=[O:5]
Reactant: Brc1cccs1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(c1ccc(Br)s1)c1c(F)c(F)cc(F)c1F
Reaction time: 2.5 h
Yield: 33.3 %

Procedure:
To a mixture of perfluorobenzoyl chloride (2.51 g, 10.9 mmol) and 2-bromothiophene (1.86 g, 11.4 mmol) in carbon disulfide (80 mL), aluminum chloride (2.90 g, 21.8 mmol) was added in portions over 10 min with vigorous mechanical stirring. The reaction mixture turned red and was stirred for 2.5 h before being quenched with water (80 mL). The organics were then separated, the aqueous layer extracted with carbon disulfide (3×50 mL), and the combined organics washed with water (3×100 mL) and dried over MgSO4. After filtration, the organics were concentrated in vacuo and the chromatographed on a silica gel column (hexane:ether=9:1) to yield 1.23 g (32%) green crystals. mp 51-54° C.; 1H NMR (DMSO): δ 7.78 (d, 2H, 3J=3.6 Hz), 7.54 (d, 2H, 3J=4.4 Hz); 19F NMR (DMSO): δ −142.1 (m, 2H), −151.6 (m, 1H), −160.6 (m, 2H) Anal. Calcd for C11H2BrF5OS: C, 37.00; H, 0.56. Found: C, 37.37; H, 0.83; MS (EI): m/z (%) 355.8 (92) [M+].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:17]=2[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]3)O1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+].I[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51]>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].CO.O1CCOCC1>[C:46]1([CH3:51])[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2[nH]1
Reactant: Cc1ccccc1I
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2cccc(-c3ccccc3C)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxylate (Paul et al. J. Am. Chem. Soc. 2006, 128, 15552-15553) (1.6 g), tri-(t-butyl)phosphonium tetrafluoroborate (0.074 g), tris(dibenzylideneacetone)dipalladium(0) (0.116 g) and cesium fluoride (2.313 g) was added ortho-iodotoluene (0.781 ml), then dioxane (200 ml) and methanol (20 ml). The reaction mixture was immediately purged with nitrogen and stirred at room temperature for 2 hours. Additional amounts of (dibenzylideneacetone)dipalladium(0) (0.116 g), ortho-iodotoluene (0.781 ml), CsF (2.313 g), and tri-(t-butyl)phosphonium tetrafluoroborate (0.074 g) were added at the same time. The resulting solution was stirred at room temperature overnight. The insoluble material was filtered off and the filtrate was concentrated and the residue was purified by flash chromatography, eluting with 0-100% dichloromethane in hexane to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>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.CC(N(C)C)=O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:12]([C:14]([CH3:20])=[C:15]([CH:17]5[CH2:19][CH2:18]5)[N:16]=4)[CH:13]=3)[C:4](=[O:21])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(NCc4ccc(Cl)cc4)cc3=O)cn12
Temperature: 120 °C
Yield: 20.3 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), 4-chlorobenzylamine (49.4 mg), xantphos (10.8 mg), tris(dibenzylideneacetone)dipalladium(0) (5.3 mg), cesium carbonate (151 mg) and DMA (2 ml) was heated at 120° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature, poured into water and extracted with EtOAc-THF. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (19.1 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol (0.177 g, 1.4 mmol) in pyridine (5 mL) was added benzene sulfonyl chloride (0.284 g, 1.6 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude material purified by reverse phase chromatography to yield the title compound (0.106 g, 29% yield) as a white solid: mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.05-8.00 (m, 3H), 7.9-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19](OC(=O)C)[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O:29][C:30](=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([S:7]([N:10]2[C:11]3[CH:19]=[CH:20][CH:21]=[C:30]([O:29][C:26](=[O:28])[CH3:27])[C:12]=3[C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(OC(C)=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cccc2c1c1ccccc1n2S(=O)(=O)c1ccccc1
Temperature: 90 °C
Yield: 87.6 %

Procedure:
An autoclave was charged under an argon flow with 1.066 g of acetic acid 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl ester (3.0 mmol, oil, crude quality), 0.57 ml of acetic anhydride (6.0 mmol), 0.92 ml of triethylamine (6.6 mmol) and 2.5 ml of a catalyst solution prepared from 6.73 mg of palladium acetate (0.030 mmol) and 78.7 mg of triphenylphosphine (0.30 mmol) in 25 ml of toluene. Then the autoclave was sealed, pressurized three times with 20 bar of carbon monoxide and vented, and finally pressurized with 50 bar of carbon monoxide. The reaction mixture was stirred magnetically and heated at 90° C. for 20 h. After cooling and venting the autoclave, the dark reaction mixture was poured onto ice water and the biphasic solution stirred vigorously for 1 h. The aqueous phase was extracted with 20 ml of toluene, whereas the toluene phase was extracted in a separatory funnel with 10 ml of water and 10 ml of brine. The combined toluene phases were dried on sodium sulfate and finally rotary evaporated (47° C., 10 mbar). The resulting brown residue was purified by chromatography on silica gel (eluent:cyclohexane/t-butyl methyl ether 2:1 vol/vol) to afford 960 mg (88%) of acetic acid 9-benzenesulfonyl-9H-carbazol-4-yl ester as a light brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:55][CH2:56][CH2:57][S:58]([CH3:61])(=[O:60])=[O:59])[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)CCCCl
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Temperature: 40 °C
Yield: 75.3 %

Procedure:
To a mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (40 mg, 0.055 mmol) in DMF (3 mL) was added 1-chloro-3-(methylsulfonyl)propane (13 mg, 0.083 mmol) followed by K2CO3 (23 mg, 0.165 mmol). The mixture was heated at 40° C. for 16 h, then cooled, poured into water and filtered to give N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (35 mg, 76%). The crude material was used directly in the next step without purification. LCMS: 845.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[K+].[F:39][C:40]([F:44])([F:43])[CH:41]=[CH2:42].CN(C)C(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][C:4]1[CH:3]=[C:2](/[CH:42]=[CH:41]/[C:40]([F:44])([F:43])[F:39])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C=CC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: Cc1cc(/C=C/C(F)(F)F)ccc1C(=O)O
Temperature: 180 °C
Reaction time: 120 h

Procedure:
A mixture of 4-bromo-2-methylbenzoic acid (25 g, 0.12 mol), tri-o-tolylphosphine (7.1 g, 0.023 mol), tetra-N-butylammonium chloride (9.7 g, 0.035 mol), potassium acetate (22.8 g, 0.232 mol), 3,3,3-trifluoroprop-1-ene (89 g, 0.93 mol), palladium acetate (1.3 g, 0.0058 mol) and N,N-dimethylacetamide (150 mL, 1.6 mol) was sealed in a Parr instrument and stirred at 180° C. for 120 h. After cooling, the reaction mixture was filtered through Celite® and the filtrate was partitioned between EtOAc and 1N HCl (pH 2-3). The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give a crude product (which contained a small amount of the correspnding (Z)-isomer).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH4-].[Na+].O>C(O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:16]=1
Reactant: O=Cc1cccnc1
Reactant: NCCCN1CCN(CCCN)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cncc(CNCCCN2CCN(CCCNCc3cccnc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 3-pyridinecarboxaldehyde (561 mg, 5.24 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 12 h, NaBH4 (1.9 g, 249.92 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified by flash chromatography on neutral aluminium oxide (CH2Cl2/MeOH).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>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]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: Brc1ccncc1
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ccncc2)C[C@@H]1C
Temperature: 120 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
1,1-Dimethylethyl (2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 55) (159 mg, 0.372 mmol), 4-bromopyridine (0.071 mL, 0.744 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (58.5 mg, 0.149 mmol), tris(dibenzylideneacetone)dipalladium(0) (68.1 mg, 0.074 mmol) and sodium tert-butoxide (107 mg, 1.116 mmol) were dissolved in 1,4-dioxane (4 mL) and the resulting mixture was stirred at 120° C. under nitrogen for 16 h then cooled to room temperature and partitioned between EtOAc and a saturated NaHCO3 aqueous solution. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by SP4 using a 50 G silica cartridge (gradient:5 to 20% (2M NH3 in MeOH) in DCM) gave 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(4-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (147 mg, 0.29 mmol, 78%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][N:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:20][N:19]=1)([O-])=O>O>[Cl:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:20][N:19]=2)=[N:7][CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: NCCCNc1ncc(Cl)cc1Cl
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCNc3ncc(Cl)cc3Cl)[nH]c2=O)cn1

Procedure:
2-(3-Aminopropylamino)-3,5-dichloropyridine (1.0 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.04 g) were fused together on an oil bath at 140° C. for 5 hr. On cooling, water was added, the pH adjusted to 7 and the resulting solid filtered off. Chromatography (silica gel, chloroform/methanol, graded elution 50:1 to 35:1) and recrystallisation from methanol afforded 2-[3-(3,5-dichloropyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone, (0.55 g; 33%) m.p. 147°-48° C.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:23]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:54]>C(O)C>[Na+:54].[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:23]=1[C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=1[O:42][CH3:43])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)[O-])cn1

Procedure:
4-{2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butanoic acid (46 mg) is dissolved in ethanol (1 ml) and thereto is added 1N-aqueous sodium hydroxide solution (60 μl) and the reaction solution is concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butanoic acid sodium salt (46 mg). MS (m/z): 744 [M−Na]−
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[F:41])(=[O:50])=[O:49])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2F)c1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 10 min. After stirring, 15-crown-5 (143 mg) and 2-fluorobenzenesulfonyl chloride (146 mg) were added dropwise and the mixture was further stirred at room temperature for 20 min. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 218 mg, 93%).
Reaction SMILES: [N:1]1[C:2](=O)[NH:3][CH:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6]2.O(Cl)[Cl:17].[P+3]>>[Cl:17][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[N:1]=1
Reactant: ClOCl
Reactant: O=c1nc2c(c[nH]1)CCc1ccccc1-2
Agent: [P+3]
Product: Clc1ncc2c(n1)-c1ccccc1CC2

Procedure:
5,6-Dihydrobenzo[h]quinazolin-2(3H)-one (2.97 g) was heated at 100° C. in phosphorus (III) oxychloride (70 mL) for 2 h. The solvent was removed under vacuum and the residue was treated with ice, followed by 1M aqueous potassium carbonate solution. The aqueous solution was extracted with a mixture of ether and ethyl acetate, dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-chloro-5,6-dihydrobenzo[h]quinazoline as a yellow solid; 1H NMR (CDCl3/MeOD4, 300 MHz) 8.86 (s, 1H), 8.16 (m, 1H), 7.25-7.35 (m, 2H), 7.15 (m, 1H), 2.85 (m, 4H) ppm; 13C NMR (CDCl3/MeOD4, 75 MHz) 162.83, 159.45, 157.40, 139.60, 132.35, 130.99, 128.38, 127.61, 127.20, 126.14, 27.39, 24.11; MS (ES) 217/219 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:11][C@H:10]2[CH2:12][OH:13])=[CH:5][CH:4]=1.Cl([O-])(=O)(=O)=O.[Li+].[N-:22]=[N+:23]=[N-:24].[Na+]>C(#N)C>[N:22]([C@H:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:11])[CH2:12][OH:13])=[N+:23]=[N-:24]
Reactant: OC[C@@H]1O[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: [N-]=[N+]=N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a mixture of ((2S,3S)-3-(4-(trifluoromethyl)phenyl)oxiran-2-yl)methanol (15.00 g, 68.8 mmol) in 400 mL ACN was added lithium perchlorate (75.3 mL, 1719 mmol). The reaction mixture was a suspension. After stirring for 15 minutes, sodium azide (12.1 mL, 344 mmol) was added, and the mixture was heated at 65° C. for 24 hours under nitrogen. The reaction mixture was then cooled, and the solvent was evaporated under reduced pressure. Distilled water (500 mL) was added, and the resulting mixture was extracted 3 times (3×400 mL) with diethyl ether. The combined ether layers were directly dried over MgSO4. After removing the solvent, a colorless oil was obtained as the desired product (14.5 g, yield=81%). 1H NMR (400 MHz, CD3OD) δ ppm 3.50-3.56 (m, 1H) 3.58-3.63 (m, 1H) 3.84-3.90 (m, 1H) 4.78 (d, J=6.53 Hz, 1H) 7.62 (d, J=8.03 Hz, 2H) 7.67-7.73 (m, 2H).