Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=1[NH2:6].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: COCc1cc([N+](=O)[O-])ccc1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCc1cc(N)ccc1N
Reaction time: 3.5 h

Procedure:
Into a Parr hydrogenation bottle previously purged with argon, are placed a solution of 2-methoxymethyl-4-nitroaniline (5.0 g, 27.5 mmol) in ethyl acetate (50 mL) and 0.25 g of 10% palladium on carbon. The bottle is mounted on a Parr shaker and hydrogenation is carried out under 50-60 psig (64.7-74.7 psi or 446-515 kPa) of hydrogen pressure. The pressure is carefully monitored for hydrogen uptake and additional hydrogen is introduced to keep the pressure above 50 psig. The hydrogenation is carried out for 3.5 hours after which the catalyst is removed by vacuum filtration. The filtrate is concentrated to about 25 mL and toluene (25 mL) is added to precipitate the product, which is collected by vacuum filtration and dried at 60° C. under vacuum. The product yield is 4.5 g. 1H-NMR (500 MHz, DMSO-d6) δ 3.23 (s, 3H), 4.11 (s, 2H), 4.21 (s, 2H), 4.24 (s, 2H), 6.33 (dd, 1H), 6.37 (d, 1H), 6.41 (d, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[N:9]1([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[CH:26][CH:27]=2)=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Reactant: OB(O)c1ccsc1
Product: O=C(c1ccc(-c2ccsc2)cc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 3-Thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 56 mg (56%). MS (ES+) 341.2
Reaction SMILES: C1CCCCC1.[N+:7]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][SH:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Si:24]([O:31][C@@H:32]([C@H:34]1[C:62](=[O:63])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:38](S(C3C=CC=CC=3)=O)[C@H:39]([CH3:40])[C@H:35]12)[CH3:33])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1>[Si:24]([O:31][C@@H:32]([C@H:34]1[C:62](=[O:63])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:38]([S:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:14][C:13]3[CH:22]=[CH:23][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=3)=[O:17])[C@H:39]([CH3:40])[C@H:35]12)[CH3:33])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
0.14 ml (0.21 mmol) of a cyclohexane solution containing 1.5M of a lithiumdiisopropylamide-tetrahydrofuran complex was added to 2 ml of an ice-cooled tetrahydrofuran suspension containing 91 mg (0.352 mmol) of a magnesium bromide-diethyl ether complex, and the resulting mixture was stirred for 10 minutes an this temperature. At the end of this time, 2 ml of a tetrahydrofuran solution containing 55 mg (0.207 mmol) of 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan were added to the mixture, which was then stirred for a further 10 minutes in an ice bath. 102 mg (0.174 mmol) of the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) were then added to the mixture, and the mixture was stirred for a further 15 minutes. At the end of this time, a saturated aqueous solution of ammonium chloride was added, and then the mixture was extracted with ethyl acetate. The resulting organic extract was washed first with water and then with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 15 g of silica gel, using a 1:19 by volume mixture of ethyl acetate and hexane as the eluent, to give 104 mg (yield 84%) of the title compound as a foam-like solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](Cl)=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoate (prepared in Step A of Example 47), but using 3-methylbutanoyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([OH:16])=[N:14][O:15][C:11]=3[C:10]=2[F:21])[CH2:3]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([CH:19]=[O:20])=[CH:17][C:12]3[C:13]([O:16][CH3:22])=[N:14][O:15][C:11]=3[C:10]=2[F:21])[CH2:3]1
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(O)noc3c2F)C[C@H](C)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-3-hydroxy-1,2-benzisoxazole-5-carbaldehyde (Intermediate 556, 0.15 g, 0.5 mmol) in acetonitrile was added K2CO3 (0.08 g, 0.6 mmol) followed by MeI (0.07 mL, 0.5 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, washed with water and extracted with EtOAc (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide the title product, along with a by-product, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-2-methyl-3-oxo-2,3-dihydro-1,2-benzoxazole-5-carbaldehyde. The mixture was used in the next step with out further purification.
Reaction SMILES: I[C:2]([F:21])([F:20])[C:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([F:5])[F:4].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CS(C)=O.Cl>O.[Cu]>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][C:3]([F:5])([F:4])[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([F:21])[F:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(I)C(F)(F)Oc1cccc(Oc2ccccc2)c1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(Oc1cccc(Oc2ccccc2)c1)C(F)(F)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The 1-iodo-2-(m-phenoxyphenoxy)-1,1,2,2-tetrafluoroethane (2.06 g, 5 mmoles) is then mixed with iodobenzene (1.12 g, 5.5 mmoles), activated copper (0.7 g, 11 mmoles) and 20 ml dimethyl sulfoxide (DMSO) and heated to 120° C. The mixture is heated and stirred at 120° C. for 16 hours and then cooled, diluted with 100 ml water, acidified with HCl and the product is extracted with ethyl acetate (2×40 ml). A colorless oil, 1-(m-phenoxyphenoxy)-2-phenyl-1,1,2,2-tetrafluoroethane, is recovered in a yield of 69 percent based on 1-iodo-2-(m-phenoxyphenoxy)-1,1,2,2-tetrafluoroethane (1.3 g). The identity of the product is confirmed by mass spectrometry. The 1-(m-phenoxyphenoxy)-2-phenyl-1,1,2,2-tetrafluoroethane has a pour point of -23° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([C:26]([CH3:31])=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>CCCCO>[CH3:31][C:26]1[C:25]2[C:29](=[CH:30][C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)=[CH:23][CH:24]=2)[NH:28][N:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(C)n[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5c(C)n[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 116 °C
Yield: 8.2 %

Procedure:
A mixture of 2-chloro-N-(3-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (260 mg, 0.574 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (251 mg, 1.15 mmol) and trimethylsilyl chloride (TMSCl) (0.150 mL, 1.19 mmol) in n-BuOH (5 mL) was heated at 116° C. for 48 h. It was then purified by HPLC to give 1-(4-(4-(4-(3-methyl-1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:9]3[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: [H][H]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OCc2ccccc2)cc1CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CCc1ccccc1

Procedure:
A solution of 4-[2-(4-benzyloxy-2-phenethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13][OH:14]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:14][CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)cc(Cl)n1
Temperature: 34 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34° C.) and is then heated to 70° C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60° C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.
Reaction SMILES: [OH-].[K+].O1CCCC1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]2[O:35]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][C@H:23]2[OH:35])=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of KOH (5.06 g, 90 mmol), water (60 ml) and tetrahydrofuran (200 ml) was added tert-butyl 4-(4-(benzyloxy)phenyl)-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate (6 g, 11.3 mmol) and the reaction mixture was stirred at room temperature overnight. It was then diluted with 200 mL water and extracted twice with 200 mL ethyl acetate. The organic layer was washed with 1.5 N HCl solution and was then dried over Na2SO4, filtered, and evaporated to dryness. The crude product 4 g, (±)-rel-(3S,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate), was used in the next step without further purification. LCMS (method F) RT 2.44 min (95% AP), m/z 382 (M−H) (negative mode); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.29-7.44 (m, 5H), 7.71 (d, J=8.4, 2H), 6.91 (d, J=8.4, 2H), 5.06 (s, 2H), 4.45 (br s, 1H), 3.80-4.20 (m, 2H), 3.70 (br s, 1H), 2.60-3.05 (m, 3H), 1.95-2.20 (m, 1H), 1.35 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[CH3:29][C:30]1[N:35]=[N:34][C:33]([N:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:42]([CH:39]3[CH2:38][CH2:37][N:36]([C:33]4[N:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=4)[CH2:41][CH2:40]3)=[O:43])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(N2CCC(C(=O)O)CC2)nn1
Product: Cc1ccc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)OC4CCC(C(F)(F)F)CC4)[C@H](c4ccc(Cl)c(Cl)c4)C3)CC2)nn1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound {(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(6-methyl-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 1-(6-methyl-pyridazin-3-yl)-piperidine-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 642.4 [M]+.
Reaction SMILES: CC1C=CC(S([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[CH2:13][CH2:12]2)(=O)=O)=CC=1.S(=O)(=O)(O)O.[OH-].[NH4+]>O>[CH3:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([CH3:25])[C:17]=1[N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(c3c(C)cc(C)cc3C)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(N2CCNCC2)c(C)c1
Yield: 69 %

Procedure:
to a stirred mixture of 180 parts of 1-[(4-methylphenyl)sulfonyl]-4-(2,4,6-trimethylphenyl)piperazine and 450 parts of water were added dropwise 675 parts of sulfuric acid. The whole was stirred and refluxed for 4 hours. After cooling, the whole was treated with an ammonium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 70 parts (69%) of 1-(2,4,6-trimethylphenyl)piperazine as a residue (intermediate 14).
Reaction SMILES: CO[C:3](=[O:21])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20].C(O)(=O)C.C(OCC)(=O)C.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[O:20]=[C:6]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]1[CH2:4][C:3]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:21]
Reactant: COC(=O)CN1C(=O)C(c2ccccc2)c2ccccc21
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C(c2ccccc2)c2ccccc21)N1CCOCC1

Procedure:
11 g of methyl(2,3-dihydro-2-oxo-3-phenyl-1-indolyl)-acetate were dissolved in 50 ml of morpholine and the mixture was heated under nitrogen on a steam bath for 9 hours and then poured into a mixture of glacial acetic acid and ethyl acetate; the aqueous phase was extracted with methylene chloride and the organic phase was dried and concentrated. The crude product was recrystallized from isopropanol. Melting point 153°-154° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][C:5]([C:11]#[N:12])=[CH:4][C:3]1=2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][N:6]1[C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[CH:4]=[C:5]1[C:11]#[N:12]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc2c([nH]1)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#Cc1cc2c(n1Cc1ccc(Cl)c(Cl)c1)CCCC2=O
Yield: 91 %

Procedure:
4-Oxo4,5,6,7-tetrahydroindol-2-carbonitrile (5.5 g) (Estep, K. G.; Synthetic Communications, 1995, 25, 507-514) in DMF (100 mL) was stirred with 3,4-dichlorobenzyl chloride (5.86 g), potassium iodide (cat.) and potassium carbonate (5.5 g) overnight until reaction was complete. The mixture was poured onto ice and partitioned between water and methylene chloride. The organic phase was washed with brine and dried (MgSO4), and the solvents removed in vacuo, to afford a pale yellow solid. Trituration with ether afforded the title compound as a white solid (8.71 g, 91%), NMR d(CDCl3) 2.20 (2H, dt), 2.50 (2H, t), 2.78 (2H, t), 5.20 (2H, s) 6.95 (1H, dd), 7.20 (2H, m), 7.45 (1H, d); M/z (+) 321 (MH+), 319.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N:19]3[CH2:24][CH2:23][N:22](C(OC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)=[N:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O>[N:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:11]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(Oc1ccccc1)N1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2c(N3CCNCC3)n[nH]c2c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a suspension of 1-benzenesulfonyl-3-(1-phenoxycarbonyl-4-piperazinyl)-1H-indazole (31.3 g, 67.7 mmol) in ethanol (500 ml) was added ,50% KOH (aq.) (100 g of KOH in 100 g H2O at room temperature. The reaction mixture was warmed to reflux for 6.5 hours and cooled to room temperature. After adjusting the pH to about two using HCl (con., 120 ml), the volatiles were removed under reduced pressure. The remaining residue was diluted with water and removed via filtration. The aqueous filtrate was washed with EtOAc and basified to pH=8 using 50% NaOH (aq.). The product was extracted into 10:1 dichloromethane/isopropylalcohol. The combined organics were dried (MgSO4), filtered, and concentrated to give 13.0 g of desired 3-piperazin-1-yl-1H-indazole as a brown solid which was used without further purification.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23].Cl>N1C=CC=CC=1>[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[C:22]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=1)=[O:23]
Reactant: CCOc1ccc(N)cc1
Reactant: O=C(Cl)c1cnc2ccccc2c1O
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1ccc(NC(=O)c2cnc3ccccc3c2O)cc1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
1.86 g of phenetidine were added to a suspension of 3 g of 4-hydroxy-3-quinoline-carboxylic acid chloride (described in French Pat. No. 2,340,735) in 40 ml of anhydrous pyridine and the mixture was stirred for 16 hours. 50 ml of aqueous 2 N hydrochloric acid solution were added to the mixture which was stirred for one hour and then was filtered. The recovered product was washed with water, dried at 180° C. under reduced pressure and was crystallized from 30 ml of acetic acid and then 10 ml of dimethylformamide to obtain 2.1 g of 4-hydroxy-N-(4-ethoxyphenyl)-3-quinoline-carboxamide in the form of crystals melting at 288° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10](I)[N:5]2[N:4]=1.[CH3:17][O-:18].[Na+]>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[C:6]2[C:7]([CH:12]=[O:13])=[CH:8][CH:9]=[C:10]([O:18][CH3:17])[N:5]2[N:4]=1
Reactant: C[O-]
Reactant: O=Cc1ccc(I)n2nc(C(F)(F)F)cc12
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reaction time: 2 h
Yield: 90.5 %

Procedure:
The compound of Example 113 (2.97 g) was dissolved in methanol (50.0 mL). To this solution, sodium methoxide (1.42 g) was added and the mixture was stirred for 2 hours under reflux. After cooling, the solvent was evaporated. Water was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was suspended in diisopropyl ether. The solid product was collected by filtration to afford the title compound as a yellowish green powder (1.93 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]12[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([NH2:26])=[N:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:35][C:36]1[C:41](B(O)O)=[CH:40][CH:39]=[CH:38][N:37]=1>O.O1CCOCC1.O>[Cl:12][C:10]1[N:9]=[CH:8][C:7]2[O:13][C:14]3[C:4]([C:5]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]([NH2:26])=[N:17]4)[C:6]=2[CH:11]=1)=[CH:3][C:2]([C:41]1[C:36]([F:35])=[N:37][CH:38]=[CH:39][CH:40]=1)=[CH:16][CH:15]=3
Reactant: OB(O)c1cccnc1F
Reactant: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=NC2(c3ccccc3O1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 100 °C

Procedure:
A microwave tube was charged with 7′-bromo-3′-chlorospiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine (0.135 g, 0.315 mmol), potassium phosphate tribasic (0.078 mL, 0.945 mmol), 2-fluoro-3-pyridineboronic acid (0.049 g, 0.346 mmol) in dioxane water (3 mL, 1:1). The reaction mixture was heated in microwave at 100° C. for 40 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate solution twice, then dried on sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography with gradient of 20-100% EtOAc/Hexane to give 3′-chloro-7′-(2-fluoropyridin-3-yl)spiro[benzo[e][1,3]oxazine-4,5′-chromeno[2,3-c]pyridin]-2-amine. This material (0.049 g, 0.110 mmol) was combined with potassium phosphate tribasic (0.027 mL, 0.330 mmol), 5,6-dihydro-2H-pyran-3-ylboronic acid (0.028 g, 0.220 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.90 mg, 5.51 μmol) in dioxane/water (1 mL, 3:1). The mixture was heated to 100° C. for 1 h. The reaction was completed and it was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with gradient of 70-100% EtOAc/Hexane to give the desired product. MS m/z=493.1 [M+H]+.