Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.CN(C=O)C>O>[Si:18]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: COc1ccc2ncc(O)cc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(O[Si](C)(C)C(C)(C)C)cc2c1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A 500 mL flask, equipped with magnetic stirrer and septum, was charged with 16.6 g crude 16 (0.095 mole), 22.1 g TBDMS-Cl (97%, 0.142 mole), 13.1 g imidazole (99%, 0.19 mole) and 240 mL DMF (distilled, added by syringe). The mixture was stirred under argon for 8 hours and then poured into 1.0 L of water and extracted with ether (3×450 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to give 36.4 g of crude (orange solid). Crystallization from Et2O-pentane (1:9) and chromatography of the mother liquor concentrate on silica gel (Et2O-pentane 1:2) gave 25.0 g of 17, 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[OH:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:13])[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])=[CH:8][CH:7]=1
Reactant: COC(=O)C(O)c1ccc(N)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Product: COC(=O)C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (4-amino-phenyl)-hydroxy-acetic acid methyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded hydroxy-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-acetic acid methyl ester, which was hydrolyzed to hydroxy-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-acetic acid in step 4, MS (ISP): m/e=509.5 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[C:4]([O:25][CH3:26])[CH:3]=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:22])=[O:23])(=[O:12])=[O:11])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1CCS(=O)(=O)Nc1ccc(C)cc1S(N)(=O)=O
Reaction time: 4 h
Yield: 56.1 %

Procedure:
Palladium on carbon (5 wt. %, 0.4 g) was added to a solution of 2-[2-(4-chloro-2-methoxy-phenyl)-ethenesulfonylamino]-5-methyl-benzenesulfonamide (0.55 g, 1.32 mmol) in ethyl acetate (20 mL) and the reaction mixture was shaken under a hydrogen atmosphere (30 psi) for 4 hours. The solution was filtered through a pad of Celite and concentrated under reduced pressure to give 0.31 g (57% yield) of the title compound.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1([N:20]2[C:24]([NH2:25])=[C:23]([C:26]#[N:27])[C:22]([CH2:28][CH3:29])=[N:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:20]2[C:24]([NH:25][C:12]([C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=[CH:3][CH:4]=3)=[O:13])=[C:23]([C:26]#[N:27])[C:22]([CH2:28][CH3:29])=[N:21]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C(Cl)c1ccnc2ccccc12
Reactant: CCc1nn(C2CCCC2)c(N)c1C#N
Agent: Cl
Product: CCc1nn(C2CCCC2)c(NC(=O)c2ccnc3ccccc23)c1C#N
Temperature: 250 °C
Yield: 101.5 %

Procedure:
4-Quinolinecarboxylic acid chloride hydrochloride (3.8 g, 16.5 mmol) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile (2.8 g, 13.7 mmol) were combined and heated in an oil bath at 250° C. for 7 minutes. The reaction mixture was cooled to room temperature and the obtained solid was collected by filtration on a glass frit and was washed with chloroform. The residue was recrystallized from ethyl acetate to afford 5.0 g (100%) of 1-cyclopentyl-3-ethyl-4-cyano-5-(4-quinoline-carboxamido)-1H-pyrazole as a white solid, m.p. 156°-161° C., after drying at 110° C. for 7 hours in high vacuum.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].[CH3:41][NH:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][N:42]([CH3:41])[C:38](=[O:39])[CH2:37][CH2:36][C:33]1[CH:32]=[CH:31][C:30]([S:2]([CH3:1])(=[O:3])=[N:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]4[O:25][CH:26]=[CH:27][C:28]=4[CH3:29])=[O:23])[CH:16]=3)[CH:10]=[N:9][CH:8]=2)=[CH:35][CH:34]=1
Reactant: CNCC(O)CO
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N(C)CC(O)CO)cc3)c2)c1
Yield: 34.6 %

Procedure:
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 3-methylamino-propane-1,2-diol (0.050 mL, 0.520 mmol) were reacted to give the title compound (0.020 g, 35%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Li]C.[Li]CCCC.CN([CH:38]=[O:39])C.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([CH:38]=[O:39])=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:27]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1nc2c(cc1C=O)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 300 mg, 0.694 mmol) in THF (10 ml) at −78° C., was added MeLi (1.6 M in Et2O, 0.434 ml, 0.694 mmol), the solution was stirred for 5 min, then n-BuLi in (1.6 M in hexane, 0.477 ml, 0.763 mmol) was added and the solution was stirred for 20 min. Then, DMF (0.322 ml, 4.16 mmol) was added, the reaction mixture was stirred at −78° C. for 1 h and then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The combined organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (40 g gold silica gel cartridge, heptanes/EtOAc 95:5 to 0:100) to give the title compound as a colorless powder. (UPLC-MS 3) tR 1.10 min; ESI-MS 382.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH3:18])=[CH:13][C:12]=2[C:32]2[N:40]=[C:39]([CH3:41])[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:56](F)(F)[S:57](O)(=[O:59])=[O:58].CS(Cl)(=O)=O>C(Cl)Cl.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([C:32]3[N:40]=[C:39]([CH3:41])[N:38]=[C:37]4[C:33]=3[N:34]=[CH:35][NH:36]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:57]([CH3:56])(=[O:59])=[O:58])[CH2:21][CH2:20]3)[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc3[nH]cnc23)cc1F
Reaction time: 1 h
Yield: 2.66 %

Procedure:
A mixture of tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (0.450 g, 0.695 mmol) and trifluoroacetic acid (0.803 mL, 10.42 mmol) in DCM (25 mL) was treated with trifluoromethanesulfonic acid (0.01 mL) and allowed to stir under inert atmosphere for 1 h. The mixture was concentrated in vacuo. The residue was diluted with DCM (10 mL), then sodium carbonate (2.50 g) was added to the mixture and allowed to stir 10 min. Then methanesulfonyl chloride (0.271 mL, 3.47 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with dichloromethane (20 mL), water (20 mL) and brine solution (10 mL). The organic layer was extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Luna column, 10 micron, C18(2), 100 Å, 250×50 mm, (Varian, 5-70% acetonitrile in water with trifluoroacetic acid additive 0.1% v/v in each solvent) and then further purified by normal phase silica-gel chromatography on an Interchim puriflash (25 g) column eluting with 10% methanol in dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-((R)-1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-2-amine (0.010 g, 0.018 mmol, 2.66% yield) as a light-yellow solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.77 (d, J=1.96 Hz, 1H) 8.39 (dd, J=12.52, 2.15 Hz, 1H) 8.32 (d, J=2.15 Hz, 1H) 8.21 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 4.04 (s, 3H) 3.67-3.73 (m, 1H) 3.26 (t, J=4.69 Hz, 4H) 2.94 (s, 3H) 2.77 (s, 3H) 2.62-2.71 (m, 4H) 1.51 (d, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 542.1 (M+H)+.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:11]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:10]=3[C:9]2=[O:24])[CH2:5][CH2:4]1)#N.[ClH:25]>C(O)(=O)C>[ClH:25].[F:23][C:21]1[CH:20]=[CH:19][C:11]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:6]3([C:9](=[O:24])[C:10]=2[CH:22]=1)[CH2:5][CH2:4][NH:3][CH2:8][CH2:7]3
Reactant: N#CN1CCC2(CC1)C(=O)c1cc(F)ccc1Sc1ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2Sc2ccccc2C12CCNCC2
Temperature: 0 °C

Procedure:
A mixture of 1.8 g of 1'-cyano-2-fluoro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine], Example 27, in 11 ml of acetic acid and 21 ml of 3 N hydrochloric acid is stirred in a 125°-130° C. bath for 20 hours. Thereafter, the mixture is diluted with 25 ml and rotary evaporated to dryness. The residue is taken up in 25 ml of water and the water is removed by rotary evaporation. The residue is taken up in 25 ml of water and the aqueous mixture is cooled to 0° C. The precipitate is collected by filtration and then washed sequentially with water and then before being dried. The product is recrystallized repeatedly from a methyl alcohol-acetone-ether mixture to provide 2-fluoro-10,11-dihydro-11-oxospiro[dibenz(b,f)thiepin-10,4'-piperidine] hydrochloride.
Reaction SMILES: [CH2:1]([C:3]1([NH:26]C(=O)OC(C)(C)C)[CH2:8][CH2:7][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@H:23]([OH:25])[CH3:24])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1)[CH3:2].[ClH:34]>ClCCl>[ClH:34].[NH2:26][C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH:6]([O:9][C:10]2[N:11]=[CH:12][N:13]=[C:14]3[C:21]=2[C:20]2[C@@H:19]([CH2:22][C@H:23]([OH:25])[CH3:24])[CH2:18][CH2:17][C:16]=2[S:15]3)[CH2:5][CH2:4]1
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CCC1(N)CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@@H](C)O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was charged with a solution of tert-butyl N-(1-ethyl-4-[[(3R)-3-[(2R)-2-hydroxypropyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (160 mg, 0.34 mmol, 1.00 equiv) in dichloromethane (6 mL) at 0° C. Then hydrochloric acid (conc., 0.5 mL) was added at this temperature and stirred for 2 h at room temperature. The reaction solution was concentrated under vacuum to give 150 mg (crude) of (2R)-1-[(3R)-12-[(4-amino-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propan-2-ol hydrochloride as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH2:28][CH2:29][CH2:30][OH:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:28][CH2:29][CH2:30][OH:31])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: NCCO
Solvent: CC#N
Product: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CNCCO)CO2

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2-aminoethanol (0.5 ml), ACN (3 ml). 1H-NMR (400 MHz, MeOD): δ 7.57 (1H, d, J 2.3), δ 7.46 (1H, d, J 2.3), δ 4.59 (1H, dd, J 11.6, 2.4), δ 4.42 (1H, m), δ 4.21 (1H, dd, J 11.6, 7.4), δ 3.71 (2H, t, J 5.3), δ 3.14 (3H, s), δ 2.97 (2H, d, J 5.8), δ 2.82 (3H, m) ppm (J-values are in Hz and shifts relative to solvent-peak at δ 4.8 ppm).
Reaction SMILES: C(NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(O)=O)C3)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:59][CH:58]=4)=[CH:51][CH:50]=3)[CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:70][CH:34]([CH3:33])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:68])[C:57]4[CH:58]=[CH:59][C:60]([CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[CH:61][CH:62]=4)=[CH:51][CH:50]=3)[CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)OC)C(C)C)C4=O)cc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN([C@H](C(=O)O)C(C)C)C4=O)cc2)cc1
Yield: 71.7 %

Procedure:
The compound of example 325 was prepared analogous to compound of example 305 by hydrolysis of compound of example 324.
Reaction SMILES: C(O[CH:9]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[C:19]([C:20](=[O:26])[CH:21](OCC)O)[C:11]=2[O:10]1)C1C=CC=CC=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH2:35][C:36]([NH2:39])([CH3:38])[CH3:37])[CH:31]=[C:32]([CH3:34])[CH:33]=1.Cl>>[CH2:20]([O:26][C:17]1[CH:18]=[C:19]([CH:20]([OH:26])[CH2:21][NH:39][C:36]([CH3:37])([CH3:38])[CH2:35][C:30]2[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=2)[C:11]2[O:10][CH2:9][C:14](=[O:15])[NH:13][C:12]=2[CH:16]=1)[C:19]1[CH:11]=[CH:12][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(C)cc(CC(C)(C)N)c1
Reactant: CCOC(O)C(=O)c1cccc2c1OC(OCc1ccccc1)C(=O)N2
Agent: Cl
Product: Cc1cc(C)cc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3c2OCC(=O)N3)c1

Procedure:
Prepared analogously to the method for Example 8(d) from 1.47 g (4.1 mmol) of benzyloxy-8-(2-ethoxy-2-hydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 0.65 g (3.7 mmol) of 2-(3,5-dimethylphenyl)-1,1-dimethylethylamine. Yield: 1.1 g (51%, hydrochloride); melting point: 220° C.-222° C.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([CH:15]=[N:16][C:17]([O:19][Si](C)(C)C)=[CH2:18])[CH:14]=1.C(OC([N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)/[C:34](=[CH:42]/[C:43]2[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=2)/[C:33]1=[O:58])=O)(C)(C)C>CO>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:32][C:33](=[O:58])[C:34]3([CH:42]([C:43]4[C:44]([O:50][C:51]([C:54]([O:56][CH3:57])=[O:55])([CH3:53])[CH3:52])=[N:45][CH:46]=[C:47]([Cl:49])[CH:48]=4)[CH2:19][C:17](=[O:18])[NH:16][CH:15]3[C:13]3[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=3[CH3:24])[C:35]2=[CH:36][CH:37]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)Oc1ncc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
To a toluene solution (50 mL) of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (18 mmol) was added E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-pyridin-3-ylmethylene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 6 mmol). Then the reaction mixture were heated at 130° C. for 2 h. After the solution was cooled to room temperature, methanol was added, and then the mixture was concentrated. Then a mixture of trifluoroacetic acid (10 mL) and dichloromethane (30 mL) was added. The reaction mixture was stirred at room temperature for 10 min. The solution was concentrated and the residue was purified by Prep-HPLC to give title compound as a white solid (170 mg).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]([CH3:13])[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O.[Cl-].[Na+]>O.CN(C)C=O>[CH3:2][O:3][N:4]([CH3:13])[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:11][CH2:12]1)=[O:6]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CON(C)C(=O)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(CC(F)(F)F)CC1
Yield: 32.2 %

Procedure:
N-Methoxy-N-methylpiperidine-4-carboxamide hydrochloride (600 mg, 2.88 mmol) in water (5 mL) was adjusted to pH 10 with 1 M aqueous sodium hydroxide and extracted with 1-butanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a colorless solid. The resulting solid (200 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (4 mL) and stirred with potassium carbonate (481 mg, 3.48 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (335 μL, 2.32 mmol) at room temperature for one day. After addition of water and saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol/chloroform=1/19→1/9 (v/v)) to give the title compound as a colorless oil (190 mg, yield 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH:23](=O)[CH3:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CC=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
In a 100 mL round-bottomed flask, 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (179 mg, 560 μmol, Eq: 1.00) and acetaldehyde (247 mg, 316 μl, 5.6 mmol, Eq: 10.0) were combined with THF (5.0 ml) to give a light yellow solution. Acetic acid (33.6 mg, 32.0 μl, 560 μmol, Eq: 1.00) was added. The reaction mixture was cooled to 0° C. Sodium triacetoxyborohydride (178 mg, 840 μmol, Eq: 1.5) was added. The reaction mixture stirred at room temperature for 2 h. The reaction was poured into water, and then saturated NaHCO3 was added to the solution until it was basic. The solution was extracted twice with EtOAc, and then the organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give a solid. The solid was triturated with ether to give 6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (121 mg, 62%). LC/MS-ESI observed [M+H]+ 348.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([C@@H:9]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>ClCCl.CN(C)C1C=CN=CC=1>[C:32]([O:22][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[CH3:8])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:34])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)NCCCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.2 %

Procedure:
A solution of N-((1R)-1-(3-hydroxypropylcarbamoyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (965 mg, 2.86 mmol) in dichloromethane (10 mL) was cooled to 0° C. 4-(dimethylamino)pyridine (35 mg, 0.29 mmol), triethylamine (0.60 mL, 4.29 mmol), and acetic acid anhydride (0.32 mL, 3.43 mmol) were added. The reaction mixture was stirred for 5 hours, while it was warming slowly to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and washed with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined and washed with saturated sodium hydrogen carbonate solution. They were dried over magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica (90 g) with ethyl acetate/dichloromethane (1:3 to 1:1) to give 890 mg of 3-((2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-phenylpropionylamino)propyl acetate.