Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C1Cc2cc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)ccc2N1
Yield: 25 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 25% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=347 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=CN=1.Cl>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:23]=[CH:24][CH:25]=[CH:20][N:19]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccn1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccccn1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
10 g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.3 g (118 mmol) of 2-aminopyridine were dissolved in 200 ml of isopropanol at 40° C. The solution was admixed with 3.96 ml (48 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 30 min. The suspension was cooled to 10° C. and the crystallized product was filtered off.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([F:24])[F:23])=[C:16]([CH3:25])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[F:23][CH:22]([F:24])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH3:13])=[CH:15][C:16]=1[CH3:25]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1OCC(F)F
Yield: 49 %

Procedure:
The title compound is prepared in 49% yield (60 mg, yellow oil) from 4-chloro-2-(1-(4-(2,2-difluoroethoxy)-3-methylphenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.27 mmol, Intermediate-28, single enantiomer) and phenyl formate (67 mg, 0.61 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[C:23]4[CH:44]=[CH:43][C:42]([O:45]CC5C=CC=CC=5)=[CH:41][C:24]=4[S:25][C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)=[O:21])=[CH:16][CH:15]=2)[CH2:5][CH2:4][O:3]1>[Pd].C1COCC1.CCO>[O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]2[O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([C:22]3[C:23]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][C:24]=4[S:25][C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:29][CH:28]=3)=[O:21])=[CH:18][CH:19]=2)[CH2:5][CH2:4][O:3]1
Reactant: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1ccc(O[C@@H]2CCCC[C@H]2N2CCOC2=O)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Reaction time: 19 h
Yield: 62 %

Procedure:
A slurry of the (±)-6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-[trans-2-(2-oxooxazolidin-3-yl)cyclohexyloxy]phenyl ketone (Part C) and an equal weight of 10% Pd/C) in a 1:1 mixture of THF-EtOH was stirred under positive hydrogen pressure (from balloon) for about 19 h. The reaction mixture was filtered through a pad of diatomaceous earth and washed with THF. The filtrate was then concentrated under reduced pressure and the residue was flash chromatographed (silica gel, 10%[10% NH40H in MeOH]/CH2Cl2) to afford the title compound in 62% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O1CCOCC1.O.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>[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)=[CH:35][CH:34]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN)cc4)cc23)CC1
Temperature: 160 °C
Yield: 30.9 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and [4-(aminomethyl)phenyl boronic acid (55 mg, 0.290 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (9.8 mg, 31%).
Reaction SMILES: [OH:1][CH:2]([CH2:37][NH:38][CH:39]1[CH2:44][C:43]([CH3:46])([CH3:45])[N:42]([CH3:47])[C:41]([CH3:49])([CH3:48])[CH2:40]1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:36])[CH2:23][NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:35])([CH3:34])[CH2:26]3)=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][CH:6]=1.C(O[C:54](=[O:56])[CH3:55])(=O)C>C1C=CC=CC=1>[C:2]([O:36][CH:22]([CH2:23][N:24]([CH:25]1[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:34])([CH3:35])[CH2:26]1)[C:54](=[O:56])[CH3:55])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([O:1][C:17](=[O:20])[CH3:16])[CH2:37][N:38]([CH:39]3[CH2:40][C:41]([CH3:49])([CH3:48])[N:42]([CH3:47])[C:43]([CH3:46])([CH3:45])[CH2:44]3)[C:5](=[O:4])[CH3:6])=[CH:6][CH:7]=2)([CH3:12])[CH3:13])=[CH:19][CH:18]=1)(=[O:1])[CH3:3]
Reactant: CN1C(C)(C)CC(NCC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CNC4CC(C)(C)N(C)C(C)(C)C4)cc3)cc2)CC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(=O)OC(COc1ccc(C(C)(C)c2ccc(OCC(CN(C(C)=O)C3CC(C)(C)N(C)C(C)(C)C3)OC(C)=O)cc2)cc1)CN(C(C)=O)C1CC(C)(C)N(C)C(C)(C)C1

Procedure:
A mixture of 1 g of 2,2-bis[4-{2-hydroxy-3-[(1,2,2,6,6-pentamethyl-4-piperidyl)amino]propoxy}phenyl]propane, obtained as described in Example 4, and 1 g of acetic anhydride in 10 ml of benzene was reacted in a similar manner to that described in Example 8, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.70 on thin layer chromatography on silica gel developed with a 9:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:34]=[C:33]([NH2:35])[N:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[N:31]=1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:35][C:33]1[N:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[N:31]=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:34]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: O=S(=O)(c1ccccc1Br)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-n1nc(C(C)(C)C)cc1Nc1ccccc1S(=O)(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 110 °C
Yield: 77 %

Procedure:
N,N-Dibenzyl-2-bromobenzenesulfonamide (from Step 1, 333 mg, 0.80 mmol), 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate C), cesium carbonate (365 mg, 1.12 mmol), Pd2dba3 (41.4 mg, 0.04 mmol), and BINAP (49.8 mg, 0.08 mmol) were dissolved in toluene (7 mL) under nitrogen, and the flask was heated at 110° C. for 20 h. The reaction mixture was cooled to rt, and the solid residue removed by filtration. The solvent was removed under reduced pressure and the residue purified via silica gel flash chromatography using EtOAc/hexane (1:12, v/v) to afford the title compound as a viscous oil (348 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.03 (s, 3H), 3.99 (s, 4H), 6.10 (s, 1H), 6.88 (m, 4H), 7.07 (m, 1H), 7.10-7.27 (m, 10H), 7.38 (d, 1H), 7.47 (t, 1H), 7.71 (s, 1H), 7.77 (d, 1H). ES-MS m/z 565.4 (MH)+; HPLC RT (min) 4.37.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[OH:26]/[N:25]=[C:9](/[C:11]1[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1)\[CH2:8][CH:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccc(=O)[nH]c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1ccc(/C(CC(c2ccccc2)c2ccccc2)=N/O)c[nH]1

Procedure:
In analogy to example 151, step 3, 5-(3,3-diphenyl-propionyl)-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI−): m/z=317.1 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH2:39]([NH:46][CH2:47][CH2:48][OH:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C>[CH2:39]([N:46]([CH2:47][CH2:48][OH:49])[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:15]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: OCCNCc1ccccc1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(N(CCO)Cc4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 2-(benzylamino)ethanol (68.2 mg, 0.45 mmol) was added and the reaction was stirred at 85° C. overnight. The solvent was evaporated under reduced pressure and the crude was purified by flash column chromatography using dichloromethane and methanol as eluent yielding tert-butyl 4-(benzyl(2-hydroxyethyl)amino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (121 mg, 48.3%). MS (ES−) m/z 554 (M−H)−
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:10][CH2:11][CH2:12]C)[CH3:9])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.Br[C:23]1C=CC(C(O)=O)=C(S(C(C)C)(=O)=O)C=1.C(NCCC)C>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]([CH2:9][CH3:23])[CH2:10][CH2:11][CH3:12])=[O:7])=[C:4]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1
Reactant: CCCCN(C)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Agent: CCCNCC
Product: CCCN(CC)C(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Yield: 80 %

Procedure:
Following the general method as outlined in Intermediate 253, starting from 4-bromo-2-(isopropylsulfonyl)benzoic acid (Intermediate 242) and N-ethyl-N-propylamine, the title compound was obtained as a pink solid in 80% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[Si]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:51][N:52]2[C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([NH2:61])[C:55]=3[C:54]([CH:62]3[CH2:64][CH2:63]3)=[N:53]2)=[N:48][C:49]=1[CH3:50])(C(C)(C)C)(C)C.[OH-].[Na+].[NH4+].[Cl-]>O.CN1C(=O)CCC1>[CH:62]1([C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][C:56]=3[NH:61][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[N:52]([CH2:51][C:47]3[CH:46]=[CH:45][C:44]([OH:43])=[C:49]([CH3:50])[N:48]=3)[N:53]=2)[CH2:63][CH2:64]1
Reactant: Cc1nc(Cn2nc(C3CC3)c3c(N)cccc32)ccc1O[Si](C)(C)C(C)(C)C
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (101 mg, 0.318 mmol) was added NMP (5 mL, distilled over oven dried MgSO4). A heat gun was used to dissolve the starting material. The reaction was cooled to 0° C. and 2,4,6-trichlorobenzoyl chloride (50.8 μL, 0.318 mmol) was added dropwise. The cold bath was removed once the addition was complete. The reaction mixture was stirred for one hour. 1-((5-(tert-Butyldimethylsilyloxy)-6-methylpyridin-2-yl)methyl)-3-cyclopropyl-1H-indazol-4-amine (100 mg, 0.245 mmol) was then added in one portion to the reaction mixture and the reaction was heated to 88° C. and stirred for 5 hours. NMP was removed by vacuum distillation until the reaction mixture became a thick oil. NaOH (3 equivalents relative to lithium salt starting material) in H2O (5 mL) was added to the thick oil. The mixture was stirred at 80° C. for 30 minutes. The mixture was cooled to ambient temperature and the pH of the dark solution was adjusted to about pH 12-13 with saturated NH4Cl aqueous solution. The mixture was cooled to 0° C. and H2O (10 mL) was added. Stirring was continued for 30 minutes, during which time a solid started to crash out. The mixture was filtered and the solid was washed with a saturated NaHCO3 solution and H2O. The solid was dissolved in DCM and dried (Na2SO4). The solution was filtered, concentrated and triturated with MTBE give the final product (49%). MS (ES+APCI) m/z=581.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([Cl:18])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2c(Cl)cccc2c1O
Product: O=C(Cl)c1cnc2c(Cl)cccc2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 9.2 g of 4-hydroxy-8-chloro-3-quinoline-carboxylic acid in 100ml of thionyl chloride was stirred at room temperature for 24 hours and wasthen vacuum filtered. The recovered precipitate was washed to obtain 0.4 g of 4 -hydroxy-8-chloro-3-quinoline-carboxylic acid chloride melting at 258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:21][CH2:22][CH2:23][NH:24][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: NCCCc1ccccc1
Product: COc1cccc2cc(C(=O)NCCCc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and 3-phenylpropylamine to give N-(3-phenylpropyl)-7-methoxybenzofuran-2-carboxamide (Compound 239a). Successively, it was formylated to give N-(3-phenylpropyl)-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 239b), then compound 239b was reacted with cyclobutylamine to give compound 239 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH2:34]>>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][NH:34][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][O:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:21]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c12

Procedure:
Prepared analogously to example 10.4 from 4-{4-fluoro-2-[(R)-(tetrahydro-pyran-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and N,N-dimethyl-1,3-propanediamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH3:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CNC(=O)c1cccc(N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1cccc(C(=O)NC)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
3-Amino-N-methylbenzamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 ml, 1.64 mmol), and DIPEA (0.43 ml, 2.47 mmol) were dissolved in acetonitrile (5 ml) and stirred under microwave irradiation into a sealed vial at 100° C. for 60 minutes (UPLC-MS: complete conversion). Acetonitrile was evaporated, and the crude residue was purified by flash chromatography (DCM/EtOAc=8/2) to obtain ethyl 2-(3-(methylcarbamoyl)phenylamino)-2-phenylacetate (475 mg, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](C=CC(OC)=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]1CCC[CH2:26]1>O.I([O-])(=O)(=O)=O.[Na+].[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:26]=[O:25])=[N:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COc1ccc2c(c1)c(C=O)nn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester [282 mg, Reference Example 21(a)] in tetrahydrofuran (4 ml) and water (1.5 ml) was treated with a solution of osmium tetroxide in water (54 μL, 4 wt %) and sodium periodate (400 mg). The reaction mixture was stirred at ambient temperature for 16 hours and then filtered. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to yield 3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester (162 mg) as a white solid. LC-MS (METHOD B): RT=2.97 minutes; 277 (M+H)+. (b) 4-Fluoro-1H-indazole-3-carbaldehyde
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][N:10]1[CH3:20].O1CCCC1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]1[CH3:20]
Reactant: CCOC(=O)c1cn(C)n(-c2ccc(F)cc2F)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Yield: 81.4 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2,4-difluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.4 g, 8.7 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (1.8 g, 83%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred 0° C. solution of 1-t-Butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine (5.2 g, 18 mmol) from Step 1 was added NaH (800 mg of a 60% suspension in mineral oil, 20 mmol). After 30 min, ethyl bromoacetate (2.2 mL, 20 mmol) was added and the reaction was warmed to ambient temperature and stirred for 2 h. The reaction was quenched by the addition of acetic acid (1 mL), and the solvents were removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 20% EtOAc-hexanes as eluant. 1-t-Butyloxycarbonyl-4-((2-ethoxycarbonylmethoxyphenyl)amino)piperidine was obtained as an oil (90% yield).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[N:32]1(C(OC(C)(C)C)=O)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCNCC2)cc1)c1ccc2oc(Cl)cc2c1

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with tert-butyl piperazine-1-carboxylate (500 mg) in MeOH (3 mL) under reflux and separated via column chromatography, followed by treatment with 1 mL trifluoroacetic acid in 3 mL CH2Cl2 and then purified by column chromatography to give the desired product (Z/E=1/1) as a white solid. m/z=503[M+1]+.