Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([C:4]1[C:5]([NH:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][C:30]4=[O:35])=[C:20]([CH:23](OC)[O:24]C)[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]>C1COCC1.O>[ClH:1].[C:2]([C:4]1[C:5]([NH:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:6][C:7]([NH:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([CH2:28][N:29]4[CH2:34][CH2:33][NH:32][CH2:31][C:30]4=[O:35])=[C:20]([CH:23]=[O:24])[N:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[N:8][CH:9]=1)#[N:3]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCNCC4=O)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCNCC4=O)c(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Concentrated hydrochloric acid (0.31 ml) was added to a solution of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 121, 250 mg, 0.371 mmol) in THF (10 ml) and water (2 ml) at room temperature. After stirring for 18 h at room temperature the reaction mixture was evaporated. The residue was purified by reversed phase HPLC (RP 2) to give the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[OH-].[Na+]>CO.[Pd]>[CH3:11][C:5]1[N:4]=[N:3][CH:2]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: Cc1cc(C(=O)O)c(Cl)nn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)cnn1
Reaction time: 3 h
Yield: 30.1 %

Procedure:
To a stirred solution of 3-chloro-6-methyl-pyridazine-4-carboxylic acid (500 mg, 2.89 mmol) in MeOH (50 mL) was added NaOH (395 mg, 9.85 mmol) in pellets, followed by 150 mg of Pd/C (10%). The reaction mixture was put under a H2 atmosphere for 3 hours (atmospheric pressure). The reaction mixture was filtered on celite, acidified with aq. HCl (pH=6), and concentrated under vacuo. Column chromatography (SiO2, CH2Cl2/MeOH 7/3) yielded 6-methyl-pyridazine-4-carboxylic acid (120 mg, 29%) as a brown solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:13][CH2:14][CH:15]([OH:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[C:29]1([CH2:35][CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[Na+].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH:15]([OH:28])[CH2:14][CH2:13][CH:2]([NH:1][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC(CCC(O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Compound VI and 4-phenyl-2-oxobutanoic acid (5 eq) were mixed with water (10 ml) and concentrated NaOH was added to raise the pH to 7.5. Ethanol was added (10 ml) and a solution of sodium cyanoborohydride (3 eq) in ethanol (4 ml) was added dropwise over 15 hours. Dowex 50W-2X (H+) (25 cc) was added with stirring. After 1 hour, the slurry was added to a column of Dowex (50 cc), the column was washed with ethanol and water and the product was eluted with 3% pyridine in water. After concentration and purfication over an LH-20 column, freeze drying gave V.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([C:16]2[O:21][C:20](=[O:22])[CH2:19][CH2:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.Cl>[CH2:3]([N:2]([CH3:1])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C1CCC=C(c2ccccc2)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 5-oxo-5-phenylpentanoic acid benzyl-methyl amide was prepared by refluxing N-methylbenzylamine (10.5 mmol) and 6-phenyl-3,4-dihydro-pyran-2-one (10.5 mmol) in toluene for one hour. The reaction was allowed to stir overnight at room temperature. It was poured into 100 mL of ethyl acetate and 100 mL of IN HCl. The organic extracts were washed with 100 mL of 1N NaOH, 100 mL of water and dried over MgSO4. The crude product was flash chromatographed (CH2Cl2 /MeOH 98/2) to afford a liquid. 1H NMR (CDCl3) δ 2.0-2.2 (m, 2 H), 2.5 (t, 2 H), 2.93/2.96 (s/s, 3 H), 3.0-3.2 (m, 2 H), 4.5/4.6 (s/s, 2 H),7.1-7.6 (m, 8 H), 7.8-8.0 (m, 2 H).
Reaction SMILES: [CH2:1]([C:4]1([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3].[OH-].[Na+].O.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:4]1([C:20]2[CH:29]=[CH:28][C:27]3[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=3[CH:21]=2)[C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2ccc(C=CC(=O)OCC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(c2ccc3c(c2)C(C)(C)CCC3(C)C)COc2ccc(C=CC(=O)O)cc21

Procedure:
A solution of ethyl 3-[3-allyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (790 mg, 1.78 mmol) and sodium hydroxide (720 mg, 17.8 mmol) in THF (20 ml) is heated to reflux for 24 h. The mixture is treated with water and ethyl acetate, and acidified to pH 1 with a concentrated hydrochloric acid solution. After separation, the organic phase is washed twice with water, dried over magnesium sulphate, and concentrated in vacuo at 40° C. in a rotary evaporator. The solid obtained is washed with heptane.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:39][OH:40]>[Cl-].[Na+].O.CN(C=O)C>[CH:10]1[C:11]2[C:12](=[CH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:39][OH:40])=[O:25])=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(C=C1c2ccccc2-c2ccccc21)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
6-(2-(9H-fluoren-9-ylidene)acetamido)hexanoic acid (335 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (147 mg, 42%) as a yellow solid. 1H NMR (DMSO-d6) δ1.19 (m, 2H, CH2), 1.30 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.92 (t, J=8.0 Hz, 2H, CH2CO), 3.24 (m, 2H, NCH2), 7.08 (s, 1H, ═CH—CO), 7.28 (m, 2H, Ar—H), 7.41 (m, 2H, Ar—H), 7.76 (m, 1H, Ar—H), 7.81 (m, 2H, Ar—H), 8.53 (t, J=4.0 Hz, 1H, CONH), 8.67 (d, J=8.0 Hz, 1H, Ar—H), 10.32 (s, 1H, NH—O). LC-MS (m/z) 351 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[N+:14]([C:17]1[CH:18]=[C:19]([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]>C(#N)C.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][S:24]([CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)(=[O:25])=[O:26]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Reactant: COCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: COCCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-metoxypropylamine (0.184 mL, 1.80 mmol) and triethylamine (0.3 mL) were added to a solution of (3-Nitrophenyl)methanesulfonyl chloride (0.35 g, 1.50 mmol) in acetonitrile (10 mL). The resulting solution was vigorously stirred for 3 h at room temperature and then diluted with cold water (30 ml), which lead to the formation of a precipitate. The precipitate was filtered off, washed with water (2×10 mL) and dried. Yield of N-(3-methoxy-propyl)-C-(3-nitro-phenyl)-methanesulfonamide 0.31 g (72%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-])=O>C(OCC)(=O)C.C(O)C.[C].[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(NCCN(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.7 %

Procedure:
10% of palladium-carbon (0.738 g) was added to a solution containing 4-{[2-(dimethylamino)ethyl]amino}-N-methyl-3-nitrobenzamide (3.679 g) in a mixture of ethyl acetate (40 ml) and ethanol (37 ml), and the mixture was stirred for 4.5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated, thereby yielding the entitled compound (2.862 g) as brown solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][N:3]=1.[CH2:10]([NH:13][CH2:14][CH:15]=[O:16])[C:11]#[CH:12]>C1C=CC=CC=1>[CH2:10]([N:13]([CH2:14][CH:15]=[O:16])[C:8]([NH:7][C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)=[O:9])[C:11]#[CH:12]
Reactant: C#CCNCC=O
Reactant: Cc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C#CCN(CC=O)C(=O)Nc1nnc(C)s1

Procedure:
A mixture of 5-methyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-propargylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-propargyl-3-(5-methyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH:4]([C:3]1[CH:6]=[C:7]([C:12]([CH3:13])=[CH:11][C:10]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:2]=1)=[O:5]
Reactant: C/C=C/C(=O)OCC
Reactant: O=Cc1ccccc1Br
Product: CCOC(=O)C=C(C)c1cccc(C=O)c1

Procedure:
Coupling of 3 bromobenzaldehyde with ethyl crotonate following the method used in Example 26 gave ethyl 3-(3-formylphenyl)but-2-enoate as a light yellow oil Yield (0.547, 23%): 1H NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 7.99 (t, J=1.6 Hz, 1H), 7.87 (dt, J=7.6, 1.3 Hz, 1H), 7.74 (m, 1H), 7.56 (t, J=7.6 Hz, 1H), 6.19 (q, J=1.2 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.61 (d, J=1.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:19])[CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:10][C:9]=2[CH3:20])=[CH:4][CH:3]=1.BrBr.[Br:23]N1C(=O)CCC1=O.P(Br)(Br)Br>>[Br:23][C:10]1[C:9]([CH3:20])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([CH3:13])[C:11]=1[C:14](=[O:19])[CH2:15][CH:16]1[CH2:17][CH2:18]1
Reactant: Cc1cc(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: BrBr
Agent: BrP(Br)Br
Product: Cc1c(Br)c(C(=O)CC2CC2)n(C)c1-c1ccc(Cl)cc1

Procedure:
Bromination of (3) usinga brominating reagent such as bromine, N-bromosuccinimide, or phosphorous tribromide (as described in Elena Dvornikova et al., Synlett, 2002, No. 7, 1152-1154) yields 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-cyclopropylethanone (4). Preferably, the bromination reaction is carried out in the presence of N-bromosuccinimide in THF.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH3:33])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:31])[C:27]([O:29]C)=[O:28])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[OH-].[Li+]>C(#N)C.O.C(OCC)(=O)C.Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:32][CH3:33])=[C:16]([CH:22]4[CH2:25][N:24]([C@H:26]([CH3:31])[C:27]([OH:29])=[O:28])[CH2:23]4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COC(=O)[C@@H](C)N1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN([C@H](C)C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of methyl (2R)-2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propanoate (chiral intermediate from example 156 step 2) (13 mg, 0.027 mmol) in acetonitrile (0.6 mL) and water (0.2 mL) was added lithium hydroxide (2.4 mg, 0.10 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and 1 M HCl solution. The organic layer was separated and dried over Na2SO4, filtered and concentrated to give the desired product (10.2 mg, 83%). LCMS calculated for C22H28ClN6O3 (M+H)+: m/z=459.2; Found: 459.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=[CH:8]2)(=[O:4])=[O:3].C1C(=O)N([Br:30])C(=O)C1>CC#N>[Br:30][C:11]1[C:12]2[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc2cc(S(C)(=O)=O)ccc2c1Br
Yield: 86 %

Procedure:
A mixture of 161 (4.47 g, 13.91 mmol) and NBS (2.72 g, 1528 mmol) in MeCN (80 mL) was stirred at reflux for 3 h, then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and the solution was washed with 10% aqueous Na2SO3 and water, dried, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2Cl2, to give tert-butyl 1-bromo-6-(methylsulfonyl)-2-naphthylcarbamate (162) (4.79 g, 86%) as a white solid: mp (MeOH) 190° C.; 1H NMR [(CD3)2SO] δ 8.95 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.08 (dd, J=9.0, 1.9 Hz, 1H), 7.96 (d, J=8.9 Hz, 1H), 3.25 (after D2O exchange, s, 3H), 1.50 (s, 9H). Anal. (C16H18BrNO4S) C, H, N.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([O:42]C(C)(C)C)=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C1C=CC=CC=1>ClCCCl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:40]([OH:42])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]4[CH:25]=[CH:24][S:23][C:22]=4[C:26]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:27])=[CH:18][C:17]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(c1ccsc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COc1ccc2c(c1)C=C(c1ccsc1C(=O)N1CCOCC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 119.3 %

Procedure:
In a 2 dram vial, dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (37.7 mg, 0.059 mmol) in 1,2-Dichloroethane (1 mL) add TFA (1 mL, 12.98 mmol) The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 1.5 hrs. Transfer reaction contents to a 25 mL pear flask using benzene to rinse. Remove volatiles in vacuuo. Dissolve product in benzene and rotovap to aid in trace TFA removal. Obtained 41 mg of title compound as a yellow brown film. A LC-MS was obtained to confirm product and the product used in the next step without further purification. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100; Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Waters Xterra, 3 mm×50 mm, S7. Retention Time=1.73 min, MS m/z 583 (MH+), m/z 581 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]=12.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:8](=[O:10])[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH2:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: COc1ccc(NC(=O)c2c(N)cccc2F)cc1
Yield: 81.7 %

Procedure:
Using the procedure described in Example 91, Part B, 6-fluoroisatoic anhydride (11 mmol) and 4-methoxyaniline (11 mmol) yielded 2.34 g (84%) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][CH:16]3[O:20]CC[O:17]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16]([OH:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2CCC1OCCO1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCC1c2ccccc2-c2ccccc21

Procedure:
3-(9-Fluorenyl)propionic acid was prepared from 2-(9-fluorenyl) ethyl-1,3-dioxolane (50.0 g, 187 mmol) which was dissolved in 20 ml of acetone and 450 ml of Jones' reagent (64 g chromic acid and 64 ml of sulfuric acid in 400 ml of water). After the reaction was complete, the acetone was evaporated, the residue taken into ethyl acetate, washed with water, and organic layer extracted with 1N sodium hydroxide which was acidified with 10% HCl to yield a tan precipitate. FTIR 1954, 1913, 1707, 1429, 1316, 1257, 1208, 948, 933, 735 cm-1. 1H NMR (300 MHz, DMSO-dis) δ 1.84 (t, 2H, J=7.5 Hz), 2.21 (m, 2H), 4.03 (t, 2H, J=5.5 Hz), 7.28-7.38 (m, 4H), 7.56 (d, 2H, J=7.0 Hz), 7.84 (d, 2H, J=7.0 Hz).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=O)[CH:6]=1.[CH2:16]([SH:19])[CH2:17][SH:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH2:16]1[S:19][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[S:18][CH2:17]1
Reactant: SCCS
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1C2=C(NC3(C=N2)SCCS3)c2ccccc21
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (0.50 g, 2.52 mmol) in benzene (10 ml), 1,2-ethanedithiol (0.63 ml, 7.56 mmol) and boron trifluoride etherate (0.31 ml, 2.52 mmol) was refluxed for 23 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with benzene and water and dried. The crude material (0.64 g) was recrystallized twice from ethanol to give 0.44 g (64%) of the title compound. M.p. 284°-290° C. 1H-NMR (DMSO-d6, δ): 3.75-3.94 (m, 4H), 7.46-7.57 (m, 2H), 7.8 (m, 2H), 7.95 (s, 1H), 12.6 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21]([OH:23])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1>CN(C=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:32])[CH3:33])[CH:26]=1)[C:21]([NH:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1)=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DIPEA (7.5 mL) was added to a suspension of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (4.5 g, 0.011 mol), HATU (8.6 g, 0.023 mol) and 2-amino-5-methylthiazole (2.46 g, 0.022 mol) in DMF (70 mL). The resulting mixture was stirred at ambient temperature for 72 hours. The DMF was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with brine (100 mL). The solution was dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound. (1.7 g).
Reaction SMILES: CO[C:3](=[O:26])[CH2:4][CH:5]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18](Br)[N:17]=1)S(C1C=CC(C)=CC=1)(=O)=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:18]2[N:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[NH:22][C:3](=[O:26])[CH2:4][CH2:5]3)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)CC(c1nc(Br)ccc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Product: O=C1CCc2nc(-c3cccnc3)ccc2N1

Procedure:
In analogy to the procedures described for the preparation of example 32 (steps [C] to [D]), the title compound was prepared using 3-(6-bromo-3-nitro-pyridin-2-yl)-3-(toluene-4-sulfonyl)-propionic acid methyl ester and 3-pyridine boronic acid as corresponding starting materials. MS: 226.1 (M+H+).
Reaction SMILES: [C:1](CC(N)=O)(=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[O:18]>>[C:17]([N:19]=[C:1]([NH:15][CH:16]([CH2:29][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)[C:17]([NH:19][C:20]1([C:27]#[N:28])[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]1)=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:16]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: NC(=O)CC(=S)c1ccccc1
Agent: Cl
Product: CC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccccc1

Procedure:
The title compound was prepared starting from thiobenzoyl acetamide and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 72, step b. MS, m/z 438=M+1.