Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[N:25]=[C:24]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:5][CH2:4]1
Reactant: N#Cc1cnc(Nc2cccc(CCl)n2)s1
Reactant: CN1CCNCCC1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2cccc(Nc3ncc(C#N)s3)n2)CCC1=O
Reaction time: 2 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.092 g, 0.028 mmol) was dissolved in 1 mL DMSO. Triethylamine (0.12 mL, 0.84 mmol) was added followed by the addition 2-(6-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.070 g, 0.28 mmol). The solution as stirred for 2 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ 8.07 (s, 1H), 7.91 (dd, 1H, J=7.5, 8.2 Hz), 7.30 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.4 Hz), 4.56 (s, 2H), 3.83 (bs, 2H), 3.64 (bs, 4H), 3.01 (s, 3H), 2.93 (bs, 2H). MS [M+H]+=343.2.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32](COCC[Si](C)(C)C)[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:10]([F:20])[CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][NH:32][C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:10]([F:20])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluoro-N-isopropylbenzamide (0.7 g, 1.19 mmol) was dissolved in methylene chloride (5.0 mL) and to this was added trifluoroacetic acid (5.0 mL) and the solution was stirred at room temperature for 1 hour. LC/MS data indicated that the main reaction component was the desired product (LCMS (M+H)+: m/z=489.2). The volatiles were removed in-vacuo and the residue was azeotropically washed with acetonitrile (3×10 mL). The resulting residue was dissolved in methanol (4 mL) followed by the addition of ethylenediamine (400 μL) and ammonium hydroxide (1.2 mL). After stirring at room temperature for 2 hours, LC/MS data indicated that the main reaction component was the desired product. The crude reaction mixture was purified by RP-HPLC (pH=2) to afford the desired product as TFA salt. LCMS (M+H)+: m/z=459.2. 1H NMR (500 MHz, CD3OD): δ 9.09 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H), 7.85 (d, J=3.7 Hz, 1H), 7.66 (t, J=8.5 Hz, 1H), 7.33 (d, J=3.8 Hz, 1H), 6.47 (dd, J=8.6, 2.2 Hz, 1H), 6.39 (dd, J=13.5, 2.2 Hz, 1H), 4.61 (d, J=8.8 Hz, 2H), 4.44 (d, J=8.8 Hz, 2H), 4.22-4.13 (m, 1H), 3.68 (s, 2H), 1.23 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Br:1]CCCC#CC1C=C(NC(C2C=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=CC=2)=O)C=CC=1.O[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([N:66]([CH3:101])[C:67]([C:69]2[CH:70]=[C:71]([S:75]([C:78]3[CH:79]=[C:80]4[C:85](=[C:86]([CH3:88])[CH:87]=3)[N:84]=[CH:83][C:82]([C:89]([NH2:91])=[O:90])=[C:81]4[NH:92][C:93]3[CH:98]=[CH:97][CH:96]=[C:95]([O:99][CH3:100])[CH:94]=3)(=[O:77])=[O:76])[CH:72]=[CH:73][CH:74]=2)=[O:68])=[CH:62][CH:61]=1>>[Br:1][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][C:63]([N:66]([CH3:101])[C:67]([C:69]2[CH:70]=[C:71]([S:75]([C:78]3[CH:79]=[C:80]4[C:85](=[C:86]([CH3:88])[CH:87]=3)[N:84]=[CH:83][C:82]([C:89]([NH2:91])=[O:90])=[C:81]4[NH:92][C:93]3[CH:98]=[CH:97][CH:96]=[C:95]([O:99][CH3:100])[CH:94]=3)(=[O:77])=[O:76])[CH:72]=[CH:73][CH:74]=2)=[O:68])=[CH:62][CH:61]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(C#CCCCBr)c5)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCO)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N(C)c5ccc(CCCCOCCCCCCBr)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 98, using Intermediate 79 in place of Intermediate 77. ES/MS calcd. for C42H48BrN4O6S+ 815.3. Found m/z=815.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:25][C:26](=[O:30])[O:27][CH2:28][CH3:29]>O>[O:27]1[C:26]2([CH2:10][CH2:5][CH:6](/[CH:13]=[CH:13]/[C:6]3[CH:7]=[CH:8][N:9]=[C:10]4[C:5]=3[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]4)[CH2:7][CH2:25]2)[O:30][CH2:29][CH2:28]1
Reactant: CCOC(C)=O
Reactant: COc1ccc2nccc(C=O)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: COc1ccc2nccc(/C=C/C3CCC4(CC3)OCCO4)c2n1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A suspension of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (2.0 g, 10.6 mmol, prepared according to WO 2006/032466) and intermediate 16.ii (4.5 g, 12.3 mmol) in 1,2-DME (60 ml) was cooled to −60° C. KHMDS (0.5M in THF, 42 ml, 20.9 mmol) was added dropwise over 1 h. The resulting black solution was allowed to reach rt over 2 h. It was diluted with water (40 ml) and EA (200 ml). The yield after work up and chromatography (Hex/EA 1:1) was 2.47 g (71%; yellow oil).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][O:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccoc3)cc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A round-boftom flash was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (200) (1.0 g, 2.8 mmol), Pd(PPh3)4, (0.323 g, 0.28 mmol), 3-furanylboronic acid (0.627 g, 5.6 mmol), aqueous 2 M Na2CO3, (1.2 g, 4.7 mL, 11.2 mmol), and DME (15 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 5 h. Reaction mixture was cooled at room temperature, diluted with Et2O (30 ml) and filtered. The filtrate was diluted with EtOAc (100 mL), washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using n-hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.887 g (92%) of the title compound 201 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H), 7.48 (t, J=1.5 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.70 (d, J=1.2 Hz, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−. Anal. Calcd for C24H24O2, C, 83.69; H, 7.02; Found: C, 82.69, H, 7.06.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]4[CH2:22][O:21]C5(CCCCC5)[O:19]4)[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([CH2:4][S:5][C:6]2[CH:7]=[C:8]([O:28][C:29]3[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=3)[C:9]([NH:12][C:13]3[S:17][N:16]=[C:15]([C@H:18]([OH:19])[CH2:22][OH:21])[N:14]=3)=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: CCO
Product: Cc1ncccc1Oc1cc(SCC2CC2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
To a solution of (S)-N-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.30 g, 0.586 mmol) in ethanol (20 mL) was added 1 M HCl (0.87 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled and concentrated in vacuo and the solid triturated with ethanol. The solid was dried in vacuo to afford (S)-1-(5-(5-(cyclopropylmethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.146 g, 0.338 mmol, 57.7% yield) as the mono HCl salt. Mass Spectrum (apci) m/z=432.0 (M+H—HCl).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1(O)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2.[C:28]1([CH2:34][O:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:8][C:9]1([NH:36][O:35][CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Reactant: NOCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(NOCc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (17.4 g) was added in one portion to a solution of 5,6,7,8-tetrahydro-5-methyl-2-(phenylmethoxy)-quinolin-5-ol (41 g), phenylmethoxyamine (47 g), and toluene (770 ml) at room temperature. The solution was stirred at room temperature for 24 hrs, and then quenched with concentrated ammonium hydroxide solution. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over potassium carbonate, filtered, and the filtrate was concentrated. Purification by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) gave 44.2 g (77%) of 5,6,7,8-tetrahydro-5-methyl-N,2-bis(phenylmethoxy)-5-quinolinamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([O:21][CH3:22])[N:14]=1>>[CH3:22][O:21][C:15]1[N:16]=[C:17]([O:19][CH3:20])[N:18]=[C:13]([CH:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]2=[O:11])[N:14]=1
Reactant: O=C1Cc2cccc(Cl)c2N1
Reactant: COc1nc(Cl)nc(OC)n1
Product: COc1nc(OC)nc(C2C(=O)Nc3c(Cl)cccc32)n1

Procedure:
7-Chloro-1,3-dihydro-2H-indol-2-one (101.5 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (152 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 99% area (181.9 g, 97% of theory).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:30][C:31]1([CH2:39]Br)[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33][CH2:32]1>CN(C=O)C>[CH:3]1([C:9]2[C:17]3[CH:16]=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][C:12]=3[N:11]3[C:10]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:39][C:31]2([CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33][CH2:32]2)[CH2:30]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
NaH (5 eq, 60% dispersion in mineral oil) was added to a degassed solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in published International patent application WO2006/046030) in DMF (0.2 M) and the solution was allowed to stir for 20 min at RT. The mixture was then placed in an oil bath preheated at 70° C., a degassed solution of 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (1.5 eq) in dry DMF (0.4M) was added and the mixture was stirred for 1 h; additional electrophile (1.5 eq) was added and stirring was continued for 3 h at 70° C. The reaction was quenched with sat. aq. NH4Cl, acidified with 1N HCl and extracted with Et2O; the organic layer was washed with H2O and brine, dried over Na2SO4 and the solvent was removed in vacuo. The crude was purified by FC (PE/EtOAc) to afford the title compound (50%) and recovered starting material (44%). (ES+) m/z 490 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:16]1([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:21]2)[CH2:18][CH2:17]1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ncn(CC2CC2)n1
Product: Cc1cn(-c2ccc(Nc3ncn(CC4CC4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-cyclopropylmethyl-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish foam (Yield=45%). MS ISP (m/e): 320.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:21]([I:22])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:23]1[CH2:27][C@@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([I:22])[C:2]([N:23]3[CH2:27][C@@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@H](O)C2)c(I)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a solution of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2, 300 mg, 0.654 mmol) and (3R,4R)-pyrrolidine-3,4-diol (88 mg, 0.850 mmol) in iPrOH (5 mL) was added DIPEA (0.228 mL, 1.307 mmol). The RM was stirred at 140° C. for 1 h and then 3 h at 130° C. The solvent was evaporated off under reduced pressure to give the crude product which was used directly without any further purification. UPLC-MS (Condition 3), tR=1.00 min, m/z=525.9/528.0 [M+H]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH2:11]1[CH2:18][C:16](=O)[C:14](=O)[CH2:13][CH2:12]1>C(O)C.C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13]3[C:12](=[CH:11][CH:18]=[C:16]4[C:14]=3[NH:9][C:6]3[C:5]4=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=3)[C:5]=2[CH:4]=1
Reactant: O=C1CCCCC1=O
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2[nH]c3c(ccc4c5cc(Br)ccc5[nH]c43)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
4-Bromophenylhydrazine hydrochloride (99%; 10.44 g, 1 eq) is introduced into a solution of 1,2-cyclohexadione (98%; 5.4 g, 1 eq) in absolute ethanol (50 ml). After adding 20 drops of glacial acetic acid, the mixture is stirred at room temperature for 1 h and then at 80° C. for 4 h. Then a further 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added to the reaction and, after a further 6 h at 80° C., another 5.3 g of 99% 4-bromophenylhydrazine hydrochloride are added. The reaction is stirred overnight. After 22 h, the mixture becomes viscous, so 150 ml of absolute ethanol and a further 3 g of 99% 4-bromophenylhydrazine hydrochloride are added. After a further 2 h at 80° C., the mixture is worked up. For this purpose, the solvent is distilled off. The residue is introduced gradually into polyphosphoric acid (50 g), heated to 120° C. and stirred for 1 h. The reaction output is added cautiously to ice-water and neutralized with 2M NaOH. The precipitate is filtered off and washed with distilled water. The residue is dried under reduced pressure. After recrystallization in glacial acetic acid, 5.8 g are obtained. Yield: 29.7%
Reaction SMILES: B.O1CCCC1.[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([C:18](O)=[O:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>O>[C:7]([O:11][C:12]([N:14]1[CH2:22][CH2:21][CH:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
Borane-tetrahydrofuran (1 M, 25 mL, 25 mmol) was added slowly to N-tert-butoxycarbonylisonipecotic acid (5.73 g, 25 mmol), as prepared in the preceding step, in tetrahydrofyiran (50 mL) at 0° C. (ice-bath) over 30 min. The mixture was stirred at 0° C. overnight and then warmed up to room temperature for 6 h. Water (10 mL) was added slowly and then K2CO3 (5 g in 50 mL water) was added. The mixture was extracted with ethyl acetate (3×50 mL). The organic phase was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as white crystals (4.55 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 1.13 (m, 2 H), 1.42 (s, 9 H), 1.67 (m, 4 H), 2.67 (t, 2 H, J=12.5 Hz), 3.46 (d, 2 H, J=3.0 Hz), and 4.09 (d, 2 H, J=3.6 Hz).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([CH3:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([CH3:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[CH2:26]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(Cc2ccc3c(C)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(O[C@H]2CC[C@H](C(C)(C)C)CC2)ccc2cc(CN3CC(C(=O)O)C3)ccc12
Temperature: 0 °C

Procedure:
To a solution of methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-methylnaphthalen-2-yl)methyl)azetidine-3-carboxylate (80 mg, 0.18 mmol) in EtOH (10 mL) was added aqueous NaOH (2 mL, 20%, 5.0 eq) and 85° C. for 1 h. Then the reaction was cooled to 0° C., the pH of the solution was adjusted to 6 using 1M HCl, concentrated and the residue was dissolved in DCM, washed with water, dried and concentrated to give the title compound as a white solid (40 mg, yield: 52%). ESI-MS (M+H+): 410.3. HPLC: 97.77% 1H NMR (400 MHz, CD3OD) δ: 8.04 (d, 1H), 7.92 (s, 1H), 7.77 (d, 1H), 7.50 (dd, 1H), 7.41 (d, 1H), 4.54 (s, 2H), 4.34-4.26 (m, 5H), 3.74-3.70 (m, 1H), 2.52 (s, 3H), 2.21-2.18 (m, 2H), 1.91-1.88 (m, 2H), 1.49-1.44 (m, 2H), 1.23-1.11 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][C@H:13]([OH:20])[C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=O)=[CH:4][CH:3]=1.CO.[ClH:23]>O1CCCC1>[ClH:23].[ClH:23].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][CH2:12][C@@H:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[OH:20])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)NC[C@H](O)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O[C@@H](CNCCc1ccc(Br)cc1)c1cccnc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]acetamide (160 g) in tetrahydrofuran (1.6 l) was added dropwise 2M borane-dimethylsulfide complex in tetrahydrofuran (716 ml) below 0° C. over 5 hours. The mixture was warmed up to 60° C. and stirred at the same temperature for 3 hours. The reaction mixture was cooled in ice bath (below 5° C.). To the cooled reaction mixture were added methanol and conc. hydrochloric acid (hydrogen gas was evolved). The mixture was heated and stirred at 60° C. for 1 hour, stood overnight at ambient temperature. The mixture was concentrated in vacuo and water was removed as azeotrope with butanol (480 ml). The concentrate was pulverized with isopropyl ether (1.5l). The precipitate was collected by filtration, washed with isopropyl ether and dried in vacuo to give (1R)-2-[[2-(4-bromophenyl)ethyl]amino]-1-(3-pyridyl)ethanol dihydrochloride (226 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20]([NH2:22])=O)[NH:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:20](=[S:32])[NH2:22])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: NC(=S)c1cc2ccc(Cl)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 6-chloro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.80 g), Lawesson's reagent (0.90 g) and tetrahydrofuran (15 ml) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.75 g, yield 91%) as yellow crystals. melting point 228-230° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C@@H:8]([CH3:12])[C:9]([NH:55][C:56]1[CH:57]=[C:58]([C:62]2[N:71]=[C:70]([NH:72][C:73]3[CH:74]=[C:75]4[C:79](=[CH:80][CH:81]=3)[N:78]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[N:77]=[CH:76]4)[C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[N:63]=2)[CH:59]=[CH:60][CH:61]=1)=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of (S)-2-(tert-butoxycarbonyl)propanoic acid (21 mg, 0.11 mmol), PyBOP® (57 mg, 0.11 mmol), DIEA (49 μL, 0.28 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 0.5 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-((S)-2-(tert-butoxycarbonyl)propanamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (95 mg, 69%).