Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([OH:16])=[O:15])[N:2]=1.ClC(OCC)=O.[Cl:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][C:29]=1[Cl:30].[H-].[Na+].C1([O-])C=CC=CC=1>O1CCCC1.C(N(CC)CC)C>[Cl:23][C:24]1[CH:25]=[C:26]([O:15][C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:16])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc(Cl)c(Cl)c1)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.5 g of β-carbolin-3-carboxylic acid in a mixture of 450 ml of dry tetrahydrofuran and 1.8 ml of triethylamine is boiled under reflux for 15 minutes and cooled to room temperature. Freshly distilled ethyl chloroformate (1.25 ml) dissolved in 50 ml of dry tetrahydrofuran is added dropwise with stirring over a period of 1 hour. The reaction mixture (1) is stirred for additionally 30 minutes. A solution of 1.9 g of 3,4-dichlorophenol in 25 ml of dry tetrahydrofuran is added to 0.5 g of a 55% sodium hydride dispersion in oil suspended in 75 ml of dry tetrahydrofuran. The solution of the phenolate is added to mixture (1). Stirring is continued for one hour, whereafter the reaction mixture is filtered and concentrated to approximately 50 ml in vacuo. Addition of water (250 ml) causes the ester to precipitate. The mixture is left at 5° C. overnight and filtered. The dry product (3.0 g; 71%) is recrystallized from xylene to give pure β-carbolin-3-carboxylic acid 3,4-dichlorophenyl ester which melts at 260°-261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33](O)=[CH:32][C:31]=2[CH3:37])=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCCC>[CH3:19][O:20][C:21](=[O:38])[C:22]1[CH:23]=[CH:24][C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]=[N:11][C:12]=3[CH:16]([CH3:18])[CH3:17])=[CH:32][C:31]=2[CH3:37])=[CH:26][CH:27]=1
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: COC(=O)c1ccc(NCc2ccc(O)cc2C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: COC(=O)c1ccc(NCc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 0° C. solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (309 mg, 1.08 mmol), 4-(4-hydroxy-2-methyl-benzylamino)-benzoic acid methyl ester (292 mg, 1.08 mmol), and tri-n-butylphosphine (344 mg, 1.70 mmol) in toluene (50 mL) is added 1,1′-(Azodicarbonyl)-dipiperidine (450 mg, 1.78 mmol). The reaction mixture is stirred for 1.5 h. The reaction mixture is diluted with heptane, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (40 g silica, gradient EtOAc/Hexane) to give 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid methyl ester (309 mg, 1.08 mmol). MS: 539.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: NCCSCc1cccnn1
Reactant: CN=C=O
Product: CNC(=O)NCCSCc1cccnn1

Procedure:
By the procedure of Example 24, 3-[(2-aminoethyl)thiomethyl]pyridazine is reacted with methyl isocyanate to give the title compound.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:11](=[C:12]4[S:19][CH:18]=[N:17][C:13]4=[CH:14][CH:15]=3)[C:10]3([C:31]4[C:22](=[CH:23][C:24]5[O:29][CH2:28][CH2:27][O:26][C:25]=5[CH:30]=4)[O:21][CH2:20]3)[C:9]2=[O:32])=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.FC(F)(F)C(O)=O>[S:19]1[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[C:13]2[N:17]=[CH:18]1)[NH:8][C:9](=[O:32])[C:10]13[C:31]2[C:22](=[CH:23][C:24]3[O:29][CH2:28][CH2:27][O:26][C:25]=3[CH:30]=2)[O:21][CH2:20]1
Reactant: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3c2ccc2ncsc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc3ncsc3c2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a solution of 6′-(4-methoxybenzyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (1.9 g, 4.0 mmol) in dichloromethane (40 mL) and trifluoroacetic acid (40 mL) was added at ambient temperature trifluoromethanesulfonic acid (1.8 mL, 20 mmol). The mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography and eluted with 50% ethyl acetate in hexanes to afford 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,8′-[1,3]thiazolo[5,4-e]indol]-7′(6′H)-one (0.65 g, 44%): 1H NMR (300 MHz, CDCl3) δ10.86 (s, 1H), 9.06 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.54 (s, 1H), 6.21 (s, 1H), 4.68 (s, 2H), 4.19-4.01 (m, 4H); MS (ES+) m/z 353.1 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH2:28])[CH2:12][CH2:11]2)=[N:2]1.[C:29]1([CH3:38])[C:30]([N:35]=[C:36]=[O:37])=[CH:31][CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[NH:28][C:36]([NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH3:38])=[O:37])[CH2:14][CH2:15]2)=[N:2]1
Reactant: COc1cc(N)c(CCN2CCN(c3nsc4ccccc34)CC2)cc1OC
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: COc1cc(CCN2CCN(c3nsc4ccccc34)CC2)c(NC(=O)Nc2ccccc2C)cc1OC
Temperature: 40 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenylamine (160 mg, 0.4 mmol) was dissolved in 4 mL methylene chloride and 2-tolyl isocyanate (49 μL, 0.4 mmol) was added. The reaction mixtures were stirred at 40° C. overnight. Methylene chloride was added to the vial and the reaction mixture was washed with water. The product was recrystallized in isopropyl alcohol. 1-{2-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4,5-dimethoxy-phenyl}-3-o-tolyl-urea (168 mg) was isolated in 100% purity @ 254 nm; LCMS (APCI): 532 [M+H]+; mp 200° C.; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.80 (m, 2H), 7.47 (t, 1H), 7.33 (t, 1H), 7.18 (t, 1H), 7.11 (m, 2H), 7.02 (t, 1H), 6.74 (s, 1H), 6.35 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.61 (t, 4H), 2.77 (m, 2H), 2.73 (m, 4H), 2.67 (m, 2H), 2.12 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:23]([C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)[OH:24])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(O)c2cccc(OC)c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (1.88 g, 8.1 mmol) and dry THF (15 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.3 mL, 8.1 mmol) and stirred for 20 min. Then a mixture of 3-methoxy-benzaldehyde (1.01 g, 7.4 mmol) in dry THF (10 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.4 mL, 44 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to oil, which was purified by flash column chromatography (EtOAc/Hexane) to give (3-ethoxy-4-methoxy-phenyl)-(3-methoxy-phenyl)-methanol as an oil (1.92 g, 90% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH2CH3), 2.17 (d, J=4 Hz, 1H, OH), 3.79 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.07 (q, J=7 Hz, 2H, CH2CH3), 5.76 (d, J=4 Hz, 1H, CH), 6.78-7.28 (m, 7H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:21][CH:20]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:34])([CH3:33])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)=O.O>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:33])([CH3:34])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC(C)(C)C)cc3)c(C)cc21
Solvent: O
Solvent: C1COCCO1
Solvent: O=CO
Product: CCOC(=O)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)c(C)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.2 %

Procedure:
A solution of 6-(4-tert-butoxycarbonylmethyl-phenylethynyl)-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 194, 0.23 g, 0.5 mmol) in 1,4-dioxane (1 mL) was treated with formic acid (3 mL) and the resulting reaction mixture was stirred at ambient temperature for 6 h. Water was added and the reaction mixture was extracted with ethyl acetate(×2). The combined organic phase was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title compound (0.15 g, 74%). 1H NMR (300 MHz, CDCl3): δ 7.48 (s, 1H), 7.46 (br d, 2H), 7.23 (br d, 2H), 6.96 (s, 1H), 4.17 (q, 2H, J=7.0 Hz), 3.73 (t, 1H, J=5.8 Hz), 3.54 (br s, 2H), 2.40 (s, 3H), 2.29-1.95 (m, 2H), 1.85-1.77 (m, 1H), 1.62-1.44 (m, 1H), 1.31 (s, 3H), 1.26 (s, 3H), 1.25 (t, 3H, buried).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O.N.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: Oc1ccc2nc(O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 115 °C
Yield: 98 %

Procedure:
A solution of 2,6-quinolinediol 10 (5 g) in POCl3 (21 ml) and DMF (3.4 ml) is stirred for 12 h at room temperature, then heated for 1 h at 115° C. The reaction is poured into water (100 ml) at 0° C. and neutralized with a 32% aqueous NH3 solution. The solid obtained by filtration is washed with acetone, and the resulting organic phase is evaporated to give 2-chloro-6-quinolinol 11 as a solid. No further purification is needed.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33]5)[C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1.CCN(C(C)C)[CH:41]([CH3:43])[CH3:42].C(OC)(OC)OC.CC(C)=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[CH:3]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[C:24]([CH:27]([N:32]5[CH2:36][CH2:35][C@H:34]([NH:37][CH:41]([CH3:43])[CH3:42])[CH2:33]5)[C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1
Reactant: N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: CC(C)=O
Solvent: COC(OC)OC
Product: CC(C)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5cccc(OCC6CC6)c5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 346 %

Procedure:
To a solution of (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (Example 5; 0.15 g, 0.27 mmol), DIEA (0.14 mL, 0.81 mmol) and trimethyl orthoformate (0.59 mL, 5.40 mmol) in methanol (6 mL) was added acetone (0.30 mL, 0.41 mmol) and the mixture stirred at ambient temperature for 18 hours. The solution was cooled to 0° C. on an ice-bath and sodium borohydride (0.02 g, 0.54 mmol) was added and the mixture stirred at ambient temperature for 1 hour, then poured in a saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried (MgSO4) filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M; 10-70% CH3CN/water gradient). The residue was stirred in methanol (0.20 mL) and treated with 2N HCl in diethyl ether (2 mL) and stirred for 30 minutes and the solvents removed under reduced pressure. The residue was dissolved in methanol (0.50 mL) and treated with dichloromethane (0.50 mL) and hexanes (0.50 mL) and concentrated under reduced pressure to afford (3S)-1-(1-(3-(8-(cyclopropylmethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-N-isopropylpyrrolidin-3-amine (0.49 g, 30%). LCMS APCI (+) m/z 525 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[NH2:16][C:17]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[NH2:16][C:17]1[N:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[C:19]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)=[O:20]
Reactant: NCc1ccc(Nc2ccccc2)cc1
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (4-aminomethyl-phenyl)-phenylamine described in Preparation Example 20 (345 mg, 1.74 mmol) and 2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in N,N-dimethylformamide (10 mL) were benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL, 3.48 mmol), and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water, and then, dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate), and the title compound (360 mg, 59%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8][CH2:7][C:6]2=1.[O:20](C(C)(C)C)[K].O=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8](=[O:20])[CH2:7][C:6]2=1
Reactant: CC(C)(C)O[K]
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: O=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)CS(=O)c1ccccc1-3

Procedure:
8-Methoxy-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (79 mg, 0.281 mmoL) in DMF (5 mL) was treated with KO-t-Bu (1.0 M in THF, 0.48 mL, 0.48 mmoL) under a flow of O2 for 6 hours. The reaction mixture was then partitioned between water and EtOAc. The EtOAc layer was washed with saturated NH4Cl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, CH2Cl2: MeOH 9:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: CO.[CH3:3][C@@H:4]1[CH:11]=[CH:10][CH2:9][C:6]2([CH2:8][CH2:7]2)[C@@H:5]1[C:12](=[O:14])[CH3:13].[NH4+].[Cl-]>CCCCC>[CH3:3][C@@H:4]1[CH:11]=[CH:10][CH2:9][C:6]2([CH2:7][CH2:8]2)[C@H:5]1[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)[C@@H]1[C@H](C)C=CCC12CC2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCCCC
Product: CC(=O)[C@H]1[C@H](C)C=CCC12CC2
Temperature: 80 °C
Yield: 56.8 %

Procedure:
Na (22.7 mg, 0.987 mmol) was added to MeOH (24 ml). The resulting solution was treated at 25° C. with rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (1.62 g, 9.97 mmol, prepared in example 11), and heated at 80° C. for 64 h. The resulting solution was cooled, diluted pentane and poured into a saturated aqueous NH4Cl solution. The aqueous phase was extracted twice with pentane and the combined organic phases were washed with a saturated aqueous NaCl solution, dried (Na2SO4) and concentrated. FC (250 g SiO2, pentane/Et2O 10:0.5) of the crude product (1.5 g) gave rel-(4S,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (930 mg, 57%) and a rel-(4R,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone/rel-(4S,5R)-1-(5-methylspiro[2.5]oct-6-en-4-yl)ethanone (60:40, 408 mg, 25%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=O.Cl.[CH3:29][NH:30][CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:29][N:30]([CH3:31])[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)=[O:3]
Reactant: CNC
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1ccc(C(=O)O)cc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
285 mg (0.8 mmol) of (Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone and 330 mg (4 mmol) of dimethylamine-hydrochloride are dissolved in 8 ml of DMF and after the addition of 385 mg (1.2 mmol) of TBTU, 184 mg (1.2 mmol) of HOBt and 1.03 g (8 mmol) of N-ethyl-N,N-diisopropylamine, the mixture is stirred for 14 hours at ambient temperature. The solution is diluted with water, the product precipitated is suction filtered, washed with water and ethanol and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7](Br)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:18]/[C:19](/[CH3:28])=[C:20](/[O:26][CH3:27])\[O:21][Si](C)(C)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:27][O:26][C:20](=[O:21])[C:19]([CH3:28])([CH3:18])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(Br)C(=O)OC(C)(C)C
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 12.9 %

Procedure:
Bromo-tert-butoxycarbonylamino-acetic acid tert-butyl ester (1.5 g, 4.8 mmol) was dissolved in 40 mL of dichloromethane and then cooled in a dry ice/acetone bath. A solution of methyl trimethylsilyl dimethylketene acetal (1.9 mL, 9.6 mmol) in dichloromethane (5 mL) was added, followed by slow addition of a solution of titanium (IV) chloride (0.57 mL, 5.28 mmol) in dichloromethane (5 mL), and then a solution of triethylamine (0.73 mL, 5.28 mmol) in dichloromethane (10 mL). The reaction mixture was warned to room temperature with stirring over 16 h. An aqueous solution of citric acid (˜11 g/100 mL) was added and the reaction mixture briefly stirred. The layers were separated and the aqueous layer was extracted once more with dichloromethane. The combined dichloromethane layers were washed with sodium bicarbonate solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 206 mg (13%) of 3-tert-butoxycarbonylamino-2,2-dimethyl-succinic acid 4-tert-butyl ester 1-methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH:25]([S:28](Cl)(=[O:30])=[O:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:25]([CH3:27])[CH3:26])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Add slowly to a solution of 2-(4-bromo-phenyl)-thiophen-3-yl amine(0.6 g, 2.36 mmol) in dry dichloromethane (10 mL) at 0° C., DBU 1.41 mL (9.45 mmol) and isopropylsulfonyl chloride (0.53 mL, 4.72 mmol) (Temp. always <0° C.). Remove the ice bath and stir the mixture at RT overnight. Add satd. aq. NH4Cl (10 mL) and extract the solution with EtOAc (2×10 mL). Dry the combined organic layers and concentrate under vacuum. Purify the crude residue by flash chromatography (Silica gel-Hexane/EtOAc 4:1) to give 0.8 g (94%) of propane-2-sulfonic acid [2-(4-bromo-phenyl)-thiophen -3-yl]-amide.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[OH-].[Na+].Cl[C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31]>CCOC(C)=O>[C:23]([C:4]1[CH:3]=[C:2]([NH:1][C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Reactant: C=C(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of tert-butyl 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (see WO 2006/071940A2, 0.64 g, 1.80 mmol) in EtOAc (6 mL) was treated with 1M aq NaOH (2.7 mL). To the stirring biphasic reaction mixture at 0° C. was added isopropenyl chloroformate (0.26 mL) dropwise over 1 min. The reaction mixture was stirred for 4 h at RT. The reaction was diluted with EtOAc (20 ml). The organic layer was washed with H2O (2×10 ml), brine (10 ml) dried (MgSO4) and concentrated to afford tert-butyl 5-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonylamino)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.69 g, 87% yield) as a light yellow foam. 1H NMR (DMSO-d6) δ 9.77 (s, 1H), 8.52 (s, 1H), 8.17 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.74 (dd, J=9, 2 Hz 1H), 6.34 (s, 1H), 4.7 (m, 2H), 1.80 (s, 3H), 1.67 (s, 9H), 1.30 (s, 9H); MS (ESI) m/z: 440.2 (M+H+).