Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[OH:12][CH:5]1[CH2:6][CH2:7][NH:8][C:9]2[N:10]=[CH:11][C:2]([C:25]3[CH:24]=[CH:23][C:22]([C:20]([N:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:21])=[CH:27][CH:26]=3)=[CH:3][C:4]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: OC1CCNc2ncc(Br)cc21
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Yield: 49 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (300 mg) was reacted with (4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methanone (450 mg) as in General Procedure 13. Basic alumina chromatography using a gradient of 0-10% methanol/ethyl acetate as the eluting solvent gave the title compound as a white foam (49% yield). LCMS: m/z=353 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.78 (m, 1H), 2.19 (s, 3H), 2.32 (bs, 4H), 3.27 (m, 1H), 3.36 (m, 1H), 3.50 (bs, 4H), 4.65 (m, 1H), 5.27 (d, J=4.8 Hz, 1H), 6.81 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.71 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H).
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][C:18]([C:21]3([CH3:26])[O:25][CH2:24][CH2:23][O:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([F:36])=[C:32]([CH:35]=1)[CH2:33]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:33][C:32]2[CH:35]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=2[F:36])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3([CH3:26])[O:22][CH2:23][CH2:24][O:25]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C3(C)OCCO3)cc2)CC1
Reactant: Fc1ccc(Cl)cc1CBr
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc(C3(C)OCCO3)cc2)CC1
Yield: 64.5 %

Procedure:
Using general procedure H, 4-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 173) (350 mg, 0.97 mmol) and 5-chloro-2-fluorobenzyl bromide (324 mg, 1.5 mmol) afforded 4-{(5-chloro-2-fluoro-benzyl)-[4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a beige solid (316 mg, 65%).
Reaction SMILES: [N-]=[N+:2]=[N-:3].[Na+].CS(Cl)(=O)=O.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[N+:2](=[C:11]1[C:10](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:19])=[N-:3]
Reactant: O=C1CC(=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: [N-]=[N+]=c1c(=O)c2ccccc2c1=O
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a suspension of sodium azide (2.4 g, 36.3 mmol) in CH3CN (73 mL) was added methanesulfonyl chloride (2.8 mL, 36.3 mmol). After stirring for 16 h, the reaction mixture was poured over a suspension of indan-1,3-dione (5.3 g, 36.3 mmol) and cesium carbonate (11.8 g, 36.3 mmol) in CH3CN (50 mL). The mixture was stirred until reaction was complete (2 h), and then filtered through Celite. The filter cake was washed with EtOAc and the organic solvents were removed in vacuo. The resulting gum was diluted with EtOAc and rinsed successively with NaOH (1N), H2O and brine. The organic layer was dried (MgSO4), evaporated and the crude oil purified by flash chromatography (SiO2, 50% hexane/EtOAc) to give 2-diazoindan-1,3-dione (2a) (2.6 g, 42% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@@:19]2([CH3:32])[N:28]=[C:27]([NH2:29])[C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[S:21](=[O:31])(=[O:30])[CH2:20]2)[CH:18]=1>>[NH2:29][C:27]1[C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[S:21](=[O:30])(=[O:31])[CH2:20][C@:19]([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])([CH3:32])[N:28]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Yield: 45.6 %

Procedure:
Prepared from 5-cyanopicolinic acid (27.3 mg, 184 μmol, Eq: 1.2) and (R)-8-(5-amino-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (50 mg, 154 μmol, Eq: 1.00) as described for example 2 (method b) to give the title compound (32 mg, 70.3 μmol, 45.7% yield) as a white foam. MS (ISP): m/z=456.5 [(M+H)+].
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])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:16]1([O:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc2cc(O)cnc2cc1OC
Reactant: OC1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2cc(OC3CCCCC3)cnc2cc1OC

Procedure:
To a THF solution (30 mL) at 0° C. is added 3-hydroxy-6,7-dimethoxyquinoline (0.237 g, 1.15 mmol), cyclohexanol (0.347 g, 3.46 mmol), Ph3P (0.908 g, 3.46 mmol). Diethylazodicarboxylate is added portionwise until the solution retained a deep red color (0.663 g, 3.81 mmol). After 4 hours the solution is concentrated and the residue chromatographed (50% EtOAc in hexanes). The product is recrystallized from isopropanol/hexanes as the HCl salt as a white solid (m.p. 229-232° C., dec.).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1)[CH2:4][CH3:5].[CH3:12][O:13][C:14](=[O:20])[C:15](C)(Br)[CH2:16][CH3:17]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([N:9]1[CH2:10][C@H:6]([CH2:3][CH2:4][CH3:5])[CH2:7][C:8]1=[O:11])[CH2:16][CH3:17]
Reactant: CCC[C@H]1CNC(=O)C1
Reactant: CCC(C)(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@@H]1CC(=O)N(C(CC)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
A slurry of 60% sodium hydride suspension in mineral oil (0.94 g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (IIIa) (2 g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0° C. then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69 g, 20.4 mmol) in tetrahydrofuran (2 mL) was added over a 20 minutes period. The reaction mixture is stirred at 0° C. until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml+10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3 g (13.2 mmol, 86%) of a mixture of epimers of compound (VIa), as a mixture respectively of epimer (VIaa) and epimer (VIab).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=2[C:7]([CH3:27])=[N:6]1)([CH3:4])[CH3:3].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C([O-])(O)=O.[Na+].O1CCOCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]=2[C:7]([CH3:27])=[N:6]1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1c(C)nn2C(C)(C)C
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cccnc2)nc2c1c(C)nn2C(C)(C)C

Procedure:
Ethyl 1-(1,1-dimethylethyl)-3-methyl-6-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.244 mmol), 3-pyridinylboronic acid (39.0 mg, 0.318 mmol), aq. saturated NaHCO3 (1 mL) and 1,4-dioxane (3 mL) were degassed with nitrogen (10 min) followed by addition of PdCl2(dppf)-CH2Cl2 adduct (9.97 mg, 0.012 mmol). The sealed mixture was irradiated (microwave) at 120° C. for 40 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (0 to 100% EtOAc/hexanes). The final product was collected as a solid, 72 mg (87%). LCMS E-S (M+H)=339.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.57 (m, 3 H), 1.90 (s, 9 H), 2.72 (s, 3 H), 4.45-4.64 (m, 2 H), 7.47 (dd, J=8.08, 4.80 Hz, 1 H), 8.03 (s, 1 H), 8.46 (dt, J=8.08, 2.02 Hz, 1 H), 8.72 (dd, J=4.80, 1.52 Hz, 1 H), 9.43 (d, J=1.52 Hz, 1 H).
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:5][SH:6])=[CH2:4].[CH3:7][C:8]([CH3:10])=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:7][C:8]1([CH3:10])[S:6][CH2:5][C:3](=[CH2:4])[CH2:2][S:1]1
Reactant: CC(C)=O
Reactant: C=C(CS)CS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: C=C1CSC(C)(C)SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Mercaptomethyl)-3-mercapto-1-propene (Z. Chem. 1975, 15, 302)(0.83 g, 6.9 mmoles) and acetone (0.51 mL) were placed in about 15 mL of dichloromethane. Then anhydrous aluminium chloride (0.32 g) was added portionwise over one minute at room temperature. The solution was stirred at room temperature for 30 minutes. The reaction was worked up by addition of 20 mL of water followed by extraction with dichloromethane. The extracts were dried and evaporated to give 0.89 g clear oil with a penetrating smell. The oil was chromatographed to give 400 mg (40%) of clear oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:35])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (70 mg, 0.110 mmol) in THF/CH3OH (1.0 mL/1.0 mL) was added 2N NaOH (0.55 mL, 1.1 mmol). The reaction mixture was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C34H31ClN4O3S: 611.2 (M+H+); Found: 612.2 (M+H+), 1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.83 (d, J=5.2 Hz, 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.08 (d, J=5.6 Hz, 1H), 8.04 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (s, 2H), 5.59 (s, 1H), 5.38 (s, 1H), 3.91 (s, 3H), 2.73 (s, 3H), 2.60 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: COC1C=[CH:7][C:6]([C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([S:21][CH3:22])[N:10]=2)=CC=1.CO[CH:25](OC)[N:26](C)[CH3:27]>CN(C=O)C.C(Cl)Cl.O>[CH3:25][N:26]([CH3:27])/[CH:7]=[CH:6]/[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]=[C:11]([S:21][CH3:22])[N:10]=1
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1c(C)nc(SC)nc1-c1ccc(OC)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc(SC)nc1/C=C/N(C)C
Temperature: 130 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To the solution of ethyl 4-(4-methoxyphenyl)-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.67 g, 1.75 mmol) in 5 mL DMF was added N,N-dimethylformamide dimethyl acetal (0.32 mL, 2.50 mmol). The reaction mixture was stirred at 130° C. for 2 hours. After monitoring the reaction by TLC was cooled to room temperature, then the mixture was diluted with DCM and water. After extracted three times by DCM from the aqueous layer, the combined organic layer was dried over MgSO4. The solution was condensed under reduced pressure yielding crude mixture (467 mg). The mixture was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([OH:25])=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(#N)C>[CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:10]=1[CH2:11][C@@H:12]([C:23]([O:25][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])[N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1cc(I)ccc1OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 7A from 420 mg (0.68 mmol) of the compound from Example 70A, 9.77 mg (0.08 mmol) of DMAP, 173 mg (1.6 mmol) of benzyl alcohol and 184 mg (0.96 mmol) of EDC in 8 ml of acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)=[N:5][N:6]=1>CO.[Pd]>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]([CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[NH2:17])=[N:5][N:6]=1
Reactant: Cc1nnc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)o1
Agent: [Pd]
Solvent: CO
Product: Cc1nnc(-c2cc(N)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A mixture of 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (20 g, 73.2 mmol) and Pd/C (0.779 g, 7.32 mmol) in MeOH (25 mL) was stirred for 12 h at 35 psi under H2 atmosphere at 25° C. Then the mixture was filtered and the filtrate was concentrated to give the residue which was crystallized with MeOH (15 mL) to yield a gray solid of 3-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)aniline (17 g, 66.4 mmol, 91% yield): 1H NMR (400 MHz, CD3OD) δ 7.46 (s, 1H), 7.42 (s, 1H), 7.07 (s, 1H), 2.61 (s, 3H); ES-LCMS m/z 244 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]([CH2:13][CH:14]([OH:16])[CH3:15])[N:10]=[C:9]3[CH2:17][CH2:18][CH2:19][C:7]([C:8]=23)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[C:12]2[N:11]([CH2:13][CH:14]([OH:16])[CH3:15])[N:10]=[C:9]3[CH2:17][CH2:18][CH2:19][C:7]([C:8]=23)=[CH:6][CH:5]=1
Reactant: CC(O)Cn1nc2c3c(ccc([N+](=O)[O-])c31)CCC2
Solvent: CCO
Product: CC(O)Cn1nc2c3c(ccc(N)c31)CCC2
Yield: 93 %

Procedure:
A solution of the product from Step B (0.85, 3.3 mmol) in ethanol was treated as described for Step D of Example 1 to provide a solid (0.71 g, 99%): m.p 129-131° C.; MS (ES) m/z 232 (M+); 1H NMR (DMSO-d6) δ 7.03 (1H, d, J=8.0 Hz), 6.72 (1H, d, J=8.0 Hz), 4.80 (1H, d, J=4.0 Hz), 4.51(2H, brs), 4.01 (3H, m), 2.78 (2H, t, J=6.0 Hz), 2.62 (2H, t, J=6.0 Hz), 2.02 (2H, m), 1.00 (3H, d, J=6.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-])=O>CO.C1CCCCC=1.[Pd]>[NH2:15][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: COC(=O)c1cc(N)c(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 83735.1 %

Procedure:
To a solution of methyl 4-methyl-3,5-dinitrobenzoate (D162) (30 g, 0.125 mmol, 1 equiv) in MeOH (150 ml) and cyclohexene (300 ml) was added 10% palladium on charcoal (50% wet, 3 g, 5% w/w) and the resulting suspension was refluxed for 7 h then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the solvent was removed in vacuo. The precipitate formed was filtered off to give methyl 3-amino-4-methyl-5-nitrobenzoate (D196) (22 g, 84%) as a yellow solid which was used in the next step without further purification. [M+H]+=211.0, RT=2.81 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[N:27][C:19]=3[CH3:18])[C:14]=1[S:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CSc1c(Cl)cc2c([nH]c3cnccc32)c1N
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CO
Product: CSc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 100 °C
Yield: 89.5 %

Procedure:
A 250 ml round-bottom flask with magnetic stirrer was charged with 6-chloro-7-methylsulfanyl-9H-β-carbolin-8-ylamine (Intermediate 28, 2.336 g, 8.86 mmol) and 2-methylnicotinic acid (3.219 g, 23.4 mmol) in 80 ml anhydrous pyridine. To the resulting reaction mixture at RT was added solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.080 g, 36.9 mmol) and the reaction mixture was heated to 100° C. (oil bath) for 2 days. The resulting mixture was cooled to RT and concentrated (rotavap) to afford a brown residue. The residue was redissolved in MeOH (50 ml), slowly added to a stirring mixture of 5:1H2O/saturated aqueous sodium bicarbonate (600 mlL) and stirred at RT for 18 hr. The precipitated solid was collected via suction filtration, washed with Et2O (2×150 ml), and air-dried to afford 3.036 g of crude N-(6-chloro-7-methylsulfanyl-9H-β-carbolin-8-yl)-2-methyl-nicotinamide as a brown solid. The crude material was purified via HPLC (yields=˜40-60%). 1H-NMR (300 MHz, DMSO-d6): δ 11.72 (1H, s) 10.50 (1H, s) 8.97 (1H, s) 8.62 (1H, dd) 8.57 (1H, s) 8.41 (1H, d) 8.33-8.27 (1H, m) 8.21 (1H, d) 2.73 (3H, s) 2.41 (3H, s). LCMS (ammonium acetate standard method) retention time=1.89 min. MS (M+H+): 383.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([N+:14]([O-])=O)=[C:8]([N+:11]([O-])=O)[CH:9]=2)[C:4]([CH3:18])([CH3:17])[C:3]1=[O:19]>CO.[Ni]>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[NH2:14])[C:4]([CH3:17])([CH3:18])[C:3](=[O:19])[C:2]2([CH3:20])[CH3:1]
Reactant: CC1(C)C(=O)C(C)(C)c2cc([N+](=O)[O-])c([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CO
Product: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Yield: 95.4 %

Procedure:
12.7 g of 1,1,3,3-tetramethyl-5,6-dinitro-2-indanone were dissolved in 500 ml of methanol in a hydrogenation flask and hydrogenated with Raney-nickel. After the H2 -uptake of 6.2 l (theory=6.15 l), the catalyst was removed by filtration under suction, the filtrate was again filtered and then evaporated in vacuo. The residue was crystallized from acetonitrile. There were obtained 9.5 g (95.5% of theory) of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone of melting point 179°-180° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3[Cl:38])=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:29]=2[Cl:38])=[C:20]([C:39]([F:42])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(C(F)(F)F)cc3Cl)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(C(F)(F)F)cc2Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 169.2 %

Procedure:
Compound 71-4 (790 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (560 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]#[C:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:16])[CH:9]=[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[CH2:27]([O:26][C:24]([C:8]1[CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH3:16])[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)c1cc(C#CCN(C)C(=O)OC(C)(C)C)cc(C(=O)OCC)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cc(CCCN(C)C(=O)OC(C)(C)C)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
To a solution of 5-(N-methyl-3-tert-butoxycarbonylaminopropyn-1-yl)-benzene-1,3-dicarboxylic acid diethyl ester (890 mg) in methanol (10 mL) was added palladium 10% on carbon (89 mg) and the solution was stirred at room temperature under an hydrogen atmosphere (1 bar) for 18 h. The solid was filtered off and solvent was removed in vacuo to afford 5-(N-methyl-3-tert-butoxycarbonylaminopropyl)-benzene-1,3-dicarboxylic acid diethyl ester (767 mg) as a yellow oil:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25]OS(C)(=O)=O)=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[C:17]([F:20])[CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2
Reactant: CNCCO
Product: CN(CCO)CCCC#Cc1cc2c(cc1F)N(C(=O)Oc1ccc(Cl)cc1)CC2

Procedure:
In analogy to example 16.10, 6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester and 2-(methylamino)ethanol were converted to yield 6-Fluoro-5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pent-1-ynyl}-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a colorless oil, MS: 430 (M, 1Cl).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]>C(OC)(C)(C)C>[O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27]
Reactant: O=C1N(C[C@@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Solvent: COC(C)(C)C
Product: O=C1N(C[C@@H]2CCCO2)c2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Yield: 64 %

Procedure:
1′-[(2S)-Tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was resolved on chiral semi-prep HPLC IA column with tert-butylmethyl ether (100%) to afford (3R)-1′-[(2S)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (64%): 1H NMR (300 MHz, CDCl3) δ7.32-6.98 (m, 4H), 6.47 (s, 1H), 6.38 (s, 1H), 4.77 (ABq, 2H), 4.51 (t, J=8.6 Hz, 2H), 4.31-4.21 (m, 1H), 3.98-3.64 (m, 4H), 3.05-2.88 (m, 2H), 2.09-1.64 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.2, 161.7, 161.2, 142.8, 132.6, 128.6, 123.6, 123.2, 120.3, 119.8, 118.8, 109.4, 93.1, 80.6, 76.9, 72.3, 68.2, 57.6, 44.6, 29.2, 29.0, 25.5; MS (ES+) m/z 363.8 (M+1).