Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([OH:27])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>C(Cl)Cl.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:14])[F:15])=[N:5][N:4]=[C:3]1[C:17]12[CH2:22][CH2:21][C:20]([C:25]([NH2:30])=[O:27])([CH2:19][CH2:18]1)[CH2:23][CH2:24]2
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(=O)O)(CC1)CC2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=O)(CC1)CC2
Reaction time: 2 h

Procedure:
A portion of carboxylic acid 1-D (0.67 g, 1.77 mmol) was suspended in methylene chloride (15 ml) and treated with 1,1′-carbonyldiimidazole (0.57 g, 3.52 mmol) at room temperature and under a nitrogen atmosphere. After 2 h, concentrated ammonium hydroxide was added (40 ml) and the reaction was stirred for 18 h. The crude mixture was diluted with water (150 ml) and extracted with 3 portions of methylene chloride (70 ml). The organic washes were combined, washed with brine, dried (Na2SO4), and stripped to yield 1-E as a white powder. MS (ESI+)=379.3 (M+1); 1H NMR (500 MHz, CDCl3): δ 7.88-7.86 (m, 1 H), 7.75-7.71 (m, 2 H), 7.54 (t, 1 H), 5.75 (s, 1 H), 5.47 (s, 1 H), 3.50 (s, 3 H), 2.22 (t, 6 H), 2.00 (t, 6 H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11]([NH:41][C:38]3[CH:37]=[CH:36][C:35]([N:32]4[CH2:31][CH2:30][N:29]([CH3:28])[CH2:34][CH2:33]4)=[CH:40][CH:39]=3)=[N:10][C:9]=2[N:18]([CH:20]2[CH2:25][CH:24]3[CH2:26][CH:21]2[CH2:22][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Product: CCOC(=O)c1cn(C2CC3CCC2C3)c2nc(Nc3ccc(N4CCN(C)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
3-(Bicyclo[2.2.1]hept-2-ylamino)-propionic acid ethyl ester (1.5 g, 7.1 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.6 g, 7.1 mmol) were combined in CH2Cl2 (20 mL) and triethylamine (1.0 g, 10 mmol) was added. After 16 h, water (10 mL) was added the organic layer was separated, dried (MgSO4), and concentrated. Chromatography (10-50% EtOAc/hexanes gradient) provided 1.8 g of 4-[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester. Sodium (30 wt % dispersion in paraffin wax, 0.55 g, 7.2 mmol) was added to t-butanol (5.0 mL) at rt. After 30 minutes, a solution of 4[bicyclo[2.2.1]hept-2-yl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.8 g, 4.4 mmol) in 20 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4), and concentrated. Recrystallization from i-PrOH provided 0.51 g of 8-bicyclo[2.2.1]hept-2-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 8-Bicyclo[2.2.1]hept-2-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.12 mmol) were combined in i-PrOH (2 mL) and heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (C-18 column, 32 mL/min 5-100% MeCN/H2O gradient over 15 min) and lyophilized to provide 11.4 mg of 8-bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.21 (s, 1H), 8.59 (s, 1H), 7.52 (d, 2H, J=8.9 Hz), 6.87 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 3.52-3.62 (m, 4H), 3.28 (br s, 2H), 2.98 (br s, 2H), 2.82 (s, 3H), 2.14-2.53 (m, 5H), 1.58-1.75 (m, 4H), 1.22-1.42 (m, 5H).
Reaction SMILES: C[CH:2]1C=C(C2C=CC=CC=2)[O:4][C:3]1=O.CC1C(=O)OC(C2C=CC=CC=2)C=1.[C:27]([CH2:35][CH:36]([CH3:49])[C:37]([N:39]1[CH:43]([C:44]([OH:46])=[O:45])[CH2:42][S:41][C:40]1([CH3:48])[CH3:47])=[O:38])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.BrBr.C([O-])(=S)C.[K+]>C(O)(=O)C.C(O)(C)C.C(N(CC)CC)C>[C:3]([CH:35]([C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:36]([CH3:49])[C:37]([N:39]1[C@H:43]([C:44]([OH:46])=[O:45])[CH2:42][S:41][C:40]1([CH3:48])[CH3:47])=[O:38])(=[O:4])[CH3:2]
Reactant: CC(CC(=O)c1ccccc1)C(=O)N1C(C(=O)O)CSC1(C)C
Reactant: CC1C=C(c2ccccc2)OC1=O
Agent: BrBr
Agent: CC([O-])=S
Agent: CC1=CC(c2ccccc2)OC1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C(C(=O)c1ccccc1)C(C)C(=O)N1[C@H](C(=O)O)CSC1(C)C

Procedure:
A mixture of 8.39 g. (0.052 mole) of L-2,2-dimethylthiazolidine-4-carboxylic acid and 5.26 g. of triethylamine is heated on a steam bath. To the mixture is added 0.052 mole of a mixture of 3-methyl-5-phenyl-2(3H)-furanone and 3-methyl-5-phenyl-2(5H)-furanone in 150 ml. of dry isopropyl alcohol. The mixture is refluxed for 144 hours and the solvent is removed in vacuo. The residue is partitioned between water and ethyl acetate. The aqueous layer is poured onto crushed ice and acidified with hydrochloric acid. The mixture is extracted with ethyl acetate and the organic layer is dried over sodium sulfate. The solvent is removed to give 4.8 g. of a yellow glass which is a mixture of [4R-(4R*,2'R*)]-3-(3-benzoyl-2-methylpropionyl)-2,2-dimethyl-4-thiazolidinecarboxylic acid and [4R-(4R*,2'S*)]-3-(3-benzoyl-2-methylpropionyl)-2,2-dimethyl-4-thiazolidinecarboxylic acid. The mixture is dissolved in acetic acid containing anhydrous hydrogen bromide gas and to the mixture is added bromine. Removal of the solvent gives a glass which is reacted with potassium thioacetate as in the procedure of Example 1 to give the product of the Example as a mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:20]1[N:24]([CH2:25][C:26]([O:28]C)=[O:27])[CH:23]=[N:22][CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+:30].[OH-].O.Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([C:20]1[N:24]([CH2:25][C:26]([O-:28])=[O:27])[CH:23]=[N:22][CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4].[Li+:30]
Reactant: COC(=O)Cn1cncc1C(C)(NC(=O)OC(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)[O-]

Procedure:
A mixture of methyl {5-[1-(tert-butoxycarbonylamino)-1-(4-cyano-3-fluorophenyl)ethyl]imidazol-1-yl}acetate, as described above in Step C, (321 mg, 0.798 mmol) and LiOH (21.0 mg, 0.877 mmol) was stirred in THF (5 mL) and H2O (1.8 mL) at ambient temperature for 1 hour. The solution was adjusted to pH≈7 by the addition of 1.0 N aqueous HCl and then concentrated in vacuo to give the desired product.
Reaction SMILES: [CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl[CH2:28][C:29]#[N:30]>CO>[CH2:10]([N:9]([CH2:28][C:29]#[N:30])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNCCCCCCCC
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCCCCCCCN(CC#N)CCCCCCCC
Yield: 70 %

Procedure:
73.9 g (0.3 mol) of di-n-octylamine were initially introduced together with 31.8 g (0.3 mol) of sodium carbonate into 240 ml of absolute ethanol. At room temperature, 22.9 g (0.3 mol) of chloroacetonitrile were added and the mixture was stirred at reflux until starting material could no longer be detected by means of thin-layer chromatography (stationary phase: silica gel; mobile phase: methanol). The reaction mixture was filtered off and the filtrate was evaporated to dryness on a rotary evaporator. The residue was subjected to fractional distillation. At 145° C. and 0.04 mbar a fraction is obtained which is pure according to NMR spectroscopy. 58.4 g (0.21 mol) of di-n-octylaminoacetonitrile were isolated in the form of a clear liquid, corresponding to a yield of 69%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:36]=[C:35]([CH3:47])[CH:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:36]=[C:35]([CH3:47])[CH:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (460 mg, 76%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH3:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:7]([C:5]1[S:6][C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=2)=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:4]=1)[CH3:8]
Reactant: CCc1nc(-c2ccc(F)cc2)c(Br)s1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(C)c2)s1
Temperature: 90 °C

Procedure:
In a microwave reactor, 100 mg (0.35 mmol) of 5-bromo-2-ethyl-4-(4-fluorophenyl)-1,3-thiazole, 100 mg (0.45 mmol) of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 1 ml of a 1M caesium carbonate solution and 28.7 mg (0.04 mmol) of [1,1′-bis(diphenylphosphino)-ferrocene/palladium(II) dichloride dichloromethane complex] in 2.5 ml of THF are, under argon, heated at 90° C. for 25 min. The reaction mixture is then filtered, the filter cake is washed with ethyl acetate (3×5 ml) and the combined filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 35 mg (24%) of the desired product; 1H-NMR(MeCN-d3) δ: 8.34 (d, 1H), 7.47 (m, 3H), 7.12 (s, 1H), 7.07 (m, 2H), 6.99 (d, 1H), 3.03 (q, 2H), 2.42 (s, 3H), 1.38 (t, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1([Cl:25])[C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:7]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:5][C:6]1([Cl:25])[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:7]1([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1)[C:6]1[CH:7]=[CH:15][C:1]([O:3][C:18](=[O:21])[CH3:17])=[CH:2][CH:8]=1
Reactant: CC(=O)Oc1ccc([C@H]2[C@@H](c3ccccc3)C2(Cl)Cl)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C2(c3ccc(OC(C)=O)cc3)C(c3ccccc3)C2(Cl)Cl)cc1

Procedure:
Acetylation of Compound 36 (0.6 g, 0.0016 mol) was performed with pyridine (0.8 mL) and acetyl chloride (0.8 mL) as described in the preparation of Compound 10. The crude product was chromatographed (silica gel; CH2Cl2 /acetone, 98:2) to provide 0.02 g colorless amorphous solid, mp 74°-75° C. The fractions eluted with CH2Cl2 /acetone (95:5) had both the acetate and the phenolic products, which were subjected to acetylation. Additional purification provided a total 0.1 g of Compound 37 (13.7%). 1H NMR (CDCl3) δ 2.26 (s, 6H, OCOCH3), 3.55 (s, 1H, ArCH), 6.96-7.66 (m, 13H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[C:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=1
Reactant: CN1CC=C(c2c[nH]c3c(F)cc(F)cc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3=CCN(C)CC3)c3cc(F)cc(F)c32)cc1

Procedure:
(8.8 mg, 54%); from 5,7-difluoro-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4g, 10 mg, 0.04 mmol) and 4-methylphenylsulfonyl chloride (11.4 mg, 0.06 mmoles) with 1M NaN(TMS)2 (60 μL, 0.06 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[CH:14][CH:15]=[CH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3cccnc3nc2-c2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Temperature: 25 °C

Procedure:
3-Phenyl-2-p-tolylpyrido[2,3-b]pyrazine (step 4) (179 mg, 0.602 mmol) under nitrogen in dry MeOH (5 ml) was treated with ammonium formate (190 mg, 3.01 mmol) and 10% palladium on carbon (64.1 mg, 0.060 mmol). The resulting mixture was heated at reflux for 16 hours. After cooling to RT, the mixture was filtered through Celite® (filter material) and the catalyst was washed with MeOH and MeOH/DCM (1:1). The filtrate was concentrated in vacuo and dissolved in DCM (50 ml). The solution was washed with water (×2) and brine (×1). The resulting organic portion was passed through a phase separating column and concentrated in vacuo to afford the titled compound;
Reaction SMILES: [I-].[CH:2]([C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([C:16]([N:18]1[CH:22]=[CH:21][N+:20]([CH3:23])=[CH:19]1)=[O:17])[CH2:9]2)=[O:3].N1(CCN)C[CH2:28][O:27][CH2:26]C1.C(N(CC)CC)C>ClCCl>[N:20]1([CH2:21][CH2:22][NH:18][C:16]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:4]=3[CH:2]=[O:3])[CH2:9]2)=[O:17])[CH2:23][CH2:28][O:27][CH2:26][CH2:19]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc2c(c1C=O)CCN(C(=O)n1cc[n+](C)c1)C2
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1C=O)CCN(C(=O)NCCN1CCOCC1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
A mixture of 3-(5-formyl-6-methoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide (321 mg, 0.75 mmol), 2-(morpholin-4-yl)-ethylamine (99.5 μL, 99.5 mg, 0.75 mmol) and triethylamine (106 μL, 76 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was stirred at room temperature for 24 h. After dilution with dichloromethane (1.0 mL), the solution was washed with brine (2×5 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography over silica, eluting with a 9:1 mixture of chloroform and methanol. In this manner the title compound (154 mg, 0.44 mmol, 58.7%) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=O.BrC1C=C2C(C=CN2C)=CC=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.O>[OH:2][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cn1ccc2ccc(Br)cc21
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2ccc(CO)cc21
Temperature: 25 °C

Procedure:
To a solution of 6-methoxycarbonyl-1-methylindole (prepared by the method of Example 1(b), but using 6-bromo-1-methylindole in place of 6-bromo-1-ethylindole, 5 g) in tetrahydrofuran (30 ml) at −70° C. under a nitrogen atmosphere, was added diisobutyl aluminium hydride (66 ml of a 1.0M solution in tetrahydrofuran) dropwise with stirring. The solution was stirred at −70° C. for 15 mins then warmed to room temperature for 2 hours. The mixture was diluted with water (100 ml) and partitioned between ethyl acetate and aqueous sodium hydroxide. The aqueous layer was re-extracted with ethyl acetate and combined organic extracts were dried (MgSO4) and evaporated to give crude product which was purified by flash column chromatography using 80% ethyl acetate/20% hexane eluant to give the subtitle compound as a clear oil which solidified on standing (4.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH2:25][C:26]1[CH:27]=[C:28]([C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1.CCN(CC)CC>C1COCC1.C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:26]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[O:37])[CH:27]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(C(=O)N2CCOCC2)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Br)cc1F)Nc1cc(C(=O)N2CCOCC2)cc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 15 %

Procedure:
Dissolve (4-bromo-2-fluoro-phenyl)-acetic acid (692 mg, 3.0 mmol) in THF (24 mL) and add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (618 mg, 3.2 mmol), stir for 10 minutes. Dissolve (3-amino-5-trifluoromethyl-phenyl)-morpholin-4-yl-methanone (740 mg, excluding excess ammonium chloride) from previous step in DCM (24 mL) with Et3N (3.3 mL, 23 mmol). Add the activated acid to the amine mixture and stir at room temperature for overnight. Dilute the resulting suspension with EtOAc and wash with saturated NaHCO3 and aqueous saturated sodium chloride successively. Dry the organic layer (MgSO4), concentrate and purify by silica gel column chromatography (EtOAc/Hexane gradient) to obtain the title compound (15% yield). LCMS (ES), m/z 491 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:27]=[C:28]([S:32]([N:35]4[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36]4)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)[N:19]2[N:18]=1)=O>CS(C)=O>[OH:40][C@H:37]1[CH2:38][CH2:39][N:35]([S:32]([C:28]2[CH:27]=[C:26]([C:25]3[N:19]4[C:20]([CH:21]=[N:22][C:17]([NH:13][C:10]5[CH:11]=[C:12]6[C:7]([CH2:6][CH2:5][N:4]6[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=5)=[N:18]4)=[CH:23][CH:24]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:36]1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(=O)(=O)N4CC[C@H](O)C4)c3)n2n1
Reactant: CC(=O)N1CCc2ccc(N)cc21
Solvent: CS(C)=O
Product: CC(=O)N1CCc2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CC[C@H](O)C6)c5)n4n3)cc21
Yield: 17 %

Procedure:
1-acetyl-6-aminoindoline and (S)-1-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonyl]-pyrrolidin-3-ol were reacted in an analogous manner to Example 881D. The mixture was then taken up in DMSO and purified by Gilson prep HPLC to afford the product as a TFA salt (16 mg, 17%). HPLC purity=94%, rt=2.636 min, LCMS=519.2 (M+H). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H0, 9.01 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H0, 7.76 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.1 Hz, 8.1 Hz, 1H), 7.52 (dd, J=8.3 Hz, 1.8 Hz, 1H), 7.27 (d, J=4.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.97 (d, J=4.9 Hz, 1H), 4.18-4.08 (m, 4H), 3.31-3.20 (m, 3H), 3.12-3.02 (m, 3H), 2.17 (s, 3H), 1.80-1.70 (m, 1H), 1.68-1.60 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]3[C:13](=[C:14]([C:17]([O:19]C)=[O:18])[C:15]=2[CH:16]=1)[CH:12]=[C:11]1[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=[CH:9]3>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]3[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=2[CH:16]=1)[CH:12]=[C:11]1[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=[CH:9]3
Reactant: COC(=O)c1c2cc(OC)ccc2nc2cc3ccccc3cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc3cc4ccccc4cc3c(C(=O)O)c2c1
Yield: 65.9 %

Procedure:
A solution of methyl 2-methoxy-benz[b]acridine-12-carboxylate (35 mg, 0.10 mmol) in 4N sodium hydroxide (3 ml) and methanol (9 ml) was stirred at 65° C. for 15 hours. The resulting mixture was evaporated under reduced pressure to dryness. The residue was dissolved in water (40 ml); the aqueous solution was acidified to pH 5 with concentrated HCl in an ice-water bath. The precipitate was collected and washed with water (5 ml), yielding 2-methoxy-benz[b]acridine-12-carboxylic acid (20 mg, 59%). Rf 0.5 (silica gel, chloroform/methanol/water 65:25:4). MS (CI, CH4: m/z 304 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1I.C(=O)([O-])[O-].[K+].[K+].[S-2:27].[Na+].[Na+]>CN(C=O)C.O.[Cu]I>[CH:4]1[C:3]2[C:11]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=3[S:27][C:2]=2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=1
Reactant: [S-2]
Reactant: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2I)c(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)sc1cc(C(=O)O)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 142.5 %

Procedure:
A mixture of 2,2′-Diiodo-biphenyl-4,4′-dicarboxylic acid (450 mg, 0.912 mmol, 1 eq.) and potassium carbonate (189 mg, 1.5 eq.) in 5 mL DMF was heated to 100° C. to give a reddish brown mixture. Sodium sulfide (36 mg, 0.5 eq.) and copper(I) iodide (17 mg, 0.1 eq.) were added and reaction mixture was heated to 150° C. under a slow stream of Ar. CuI (100 mg) was added and followed by sodium sulfide (100 mg). The reaction was kept at 150° C. overnight. The reaction mixture was diluted with 25 mL water and active carbon (10 g) was added. The mixture was refluxed for 10 minutes then filtered through CELITE pad into 6N HCL (50 mL) and washed with water. The solid was formed and cooled to room temperature and filtered and washed with and dried to give product Dibenzothiophene-3,7-dicarboxylic acid (179 mg, 72%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]([Cl:36])=[O:35]>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:29]5)=[O:35])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: O=C(Cl)C1CCCO1
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCCO4)c3)c2s1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 32.5 mg (0.24 mmol) of tetrahydrofuran-2-carbonyl chloride are reacted together by general method F. 40.9 mg (68.1% of theory) of the title compound are obtained.