Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:8][CH:7]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:43])=[O:2])=[CH:7][CH:8]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(OCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenoxy)-acetic acid methyl ester (45 mg, 0.071 mmol) in THF (3 mL) was added LiOH monohydrate (13 mg, 0.30 mmol) in water (2 mL) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-phenoxy)-acetic acid as a white solid (36 mg, 80%). MS (ES+) m/z [(M+H)+]: 614
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:17][C:18](O)=[O:19].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[CH2:52][NH:51][CH2:50]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[F:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[CH2:52][N:51]([C:18](=[O:19])[CH2:17][N:3]1[CH2:4][CH2:5][CH:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[C:2]1=[O:1])[CH2:50]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(C(F)(F)F)cc2)C1=O)N1Cc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)acetic acid from Example 266D for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-fluoroisoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.61 (d, J=8.2, 2H), 7.46 (d, J=8.2, 2H), 7.32-7.16 (m, 1H), 7.06-6.89 (m, 2H), 4.82 (dd, J=8.7, 15.1, 4H), 4.34-4.13 (m, 2H), 3.83 (t, J=8.9, 1H), 3.77-3.60 (m, 2H), 2.72-2.53 (m, 1H), 2.22 (ddd, J=8.5, 12.9, 16.1, 1H); MS (DCI) m/z 407.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH:20]=1)(=[O:5])=[O:4]
Reactant: CN1CCC(=O)CC1
Reactant: CNS(=O)(=O)CCc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Temperature: 40 °C

Procedure:
2-(1H-indol-5-yl)-ethanesulfonic acid methylamide (100 g) was dissolved in ethanol (1000 ml) and N-methyl-4-piperidone (200 ml) was added thereto at 25° C. and a solution of trifluoroacetic acid in ethanol (10 ml in 100 ml) was added over a period of 1 hour. The reaction mass was refluxed for 18-24 hours and cooled to 40° C. The reaction mass was concentrated under vacuum to obtain a residue and water (1500 ml) was added. The mixture was cooled to 10-15° C. and pH of the reaction mass was adjusted to 8 using 5% sodium bicarbonate solution and stirred. The resulting solid was filtered and dried at 50-55° C. under vacuum to obtain title compound (Yield: 93 g, HPLC Purity: 99%)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][C:13]([F:18])([F:17])[CH:14]([F:16])[F:15])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].[N+](C1C=CC=CC=1N)([O-])=O.BrBr.O>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]([F:18])([F:17])[CH:14]([F:15])[F:16]
Reactant: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: BrBr
Agent: Nc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(OC(F)(F)C(F)F)cc1N
Reaction time: 0.17 h

Procedure:
10.5 Grams of 5-bromo-2-nitro-4-(1',1',2',2'-tetrafluoroethoxy)aniline [i.e. the o-nitroaniline compound (VI) containing bromine as the substituent X] was dissolved in a mixed solvent of 25 ml of ethyl acetate and 25 ml of acetic acid. The resulting solution was dropwise added to a suspension of 5.0 g of iron powders in a mixed solution of 7 ml of acetic acid and 50 ml of water while maintaining the temperature at 45°-70° C. Thereafter, stirring was continued for 10 minutes within the same temperature range. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and water in this order, dried over anhydrous magnesium sulfate and concentrated to obtain 9.5 g of 4-bromo-5-(1',1',2',2'-tetrafluoroethoxy) -1,2-benzenediamine. 1H-NMR (CDCl3): δ(ppm) 6.78(1H, s), 6.60(1H), 5.90(1H, tt, J=3, 52 Hz), 3.45(4H, broad)
Reaction SMILES: Cl.[CH3:2][NH:3][N:4]=[CH:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH:20]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:19][CH2:18][C:17]=3[CH:28]=2)=[O:11])=[CH:8][CH:7]=1.C(O)C.[OH-].[Na+]>O.C(O)(=O)C>[CH3:2][NH:3][N:4]=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[CH2:19][CH2:18][C:17]=3[CH:28]=2)=[O:11])=[CH:29][CH:30]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NNC)cc3)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 207 mg (0.48 mmol) of the ester from Example 57 were given 4 ml ethanol, 0.5 ml 2 N aqueous sodium hydroxide, and three drops of water, and the mixture was stirred overnight at room temperature. A precipitate was formed. It was brought to pH 5 with 2 N acetic acid, and the title compound was filtered with suction, washed with water and with ethanol, successively, and dried in vacuo. Yield: 0.12 g (68%) of a pale yellow powder, m.p. 275-276° C. (dec.).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)[CH3:20].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:7]([O:8][C:9]([N:21]([CH2:19][CH3:20])[CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:26][CH2:27]1)=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN(C(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 63 %

Procedure:
A 50% Cbz-Cl-toluene solution (20.87 ml, 61.40 mmol, 2.0 eq) was added dropwise at 0° C. to a mixture of tert-butyl 4-(ethylamino)piperidine-1-carboxylate (7.0 g, 30.70 mmol, 1.0 eq) and K2CO3 (12.71 g, 92.10 mmol, 3.0 eq) in DCM (100 ml) and the mixture was stirred for 14 hours at RT. The reaction mixture was diluted with DCM (200 ml), washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 20% ethyl acetate in hexane). Yield: 63% (7.0 g, 19.33 mmol)
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]5[NH:24][C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][CH:28]=[CH:27][CH:26]=6)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:35]=[C:36]([C:40]2[N:45]=[C:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:43]=[C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:41]=2)[CH:37]=[CH:38][CH:39]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:52]1([C:42]2[CH:43]=[C:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:45]=[C:40]([C:36]3[CH:35]=[C:34]([N:24]4[C:23]5[CH:22]=[CH:21][C:20]([C:16]6[CH:17]=[CH:18][C:19]7[N:7]([C:1]8[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=8)[C:8]8[C:13]([C:14]=7[CH:15]=6)=[CH:12][CH:11]=[CH:10][CH:9]=8)=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:39]=[CH:38][CH:37]=3)[N:41]=2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccccc6c5c4)ccc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3cccc(-n4c5ccccc5c5cc(-c6ccc7c(c6)c6ccccc6n7-c6ccccc6)ccc54)c3)n2)cc1

Procedure:
22.00 g (53.86 mmol) of 9-phenyl-9H,9′H-[3,3′]bicarbazolyl 26, 22.93 g (59.24 mmol) of 2-(3-bromophenyl)-4,6-diphenylpyrimidine 14 and 15.81 g (164.47 mmol) of NaOtBu are suspended in 820 ml of p-xylene. 244.79 mg (1.09 mmol) of Pd(OAc)2 and 3.3 ml of a 1M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 19 h. After cooling, the organic phase is separated off, washed three times with 100 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield is 23.10 g (60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.Cl[C:26](=[O:43])[CH2:27][C:28]([NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32]1)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:26](=[O:43])[CH2:27][C:28]([NH:30][CH:31]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:32]2)=[O:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)CC(=O)Cl)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=O)CC(=O)NC4CCN(C(=O)OC(C)(C)C)C4)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
To a solution of the amine 9 (80 mg, 0.235 mmol), acid 35 (64 mg, 0.235 mmol) and BOP (114.6 mg, 0.254 mmol) in DMF (2.4 mL) was added DIPEA (0.164 mL, 0.941 mmol) and the mixture stirred 2 h at room temperature. EtOAc (100 mL) and water (50 mL) were added and the mixture was filtered through a paper filter. The organic phase was collected, washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent EtOAc/MeOH 7:1) giving tert-butyl 3-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylamino)-3-oxopropanamido)pyrrolidine-1-carboxylate (35a, 29.7 mg, 21% yield) as a glassy solid. MS (m/z): 595.1 (M+H). This material was dissolved in a solution of TFA (0.5 mL) and DCM (0.5 mL) and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was lyophilized. The resultant solid was purified by preparative HPLC (Aquasil C-18 column, gradient: MeOH 60% to MeOH 95% in water) to afford the title compound 36 as tris-trifluoroacetate salt (13.9 mg, 35%), creamy fluffy solid. 1H NMR (DMSO-d6) δ (ppm): 10.51 (s, 1H), 8.81 (bs, 1H), 8.72 (bs, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.47 (d, J=6.3 Hz, 1H), 7.86 (m, 1H), 7.58 (s, 1H), 7.50 (t, J=9.0 Hz, 1H), 7.40 (m, 1H), 7.31 (s, 1H), 6.76 (d, J=5.4 Hz, 1H), 4.29 (m, 1H), 3.82 (s, 3H), 3.40 (m, 1H), 3.36-3.20 (m, 4H), 2.99 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H). MS (m/z): 495.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([N:15]3[CH:20]4[CH2:21][CH2:22][CH:16]3[CH2:17][CH:18]([OH:23])[CH2:19]4)=[O:14])=[CH:12][C:7]=2[N:6]=[CH:5]1.CCN(C(C)C)C(C)C.[O:33]=[S:34]1(=[O:43])[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1>C1COCC1>[OH:23][CH:18]1[CH2:19][CH:20]2[N:15]([C:13]([C:11]3[CH:10]=[CH:9][C:8]4[N:4]([CH2:3][CH2:2][NH:1][C:40]([N:37]5[CH2:38][CH2:39][S:34](=[O:43])(=[O:33])[CH2:35][CH2:36]5)=[O:41])[CH:5]=[N:6][C:7]=4[CH:12]=3)=[O:14])[CH:16]([CH2:22][CH2:21]2)[CH2:17]1
Reactant: NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCn1cnc2cc(C(=O)N3C4CCC3CC(O)C4)ccc21)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
To a solution of [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-methanone (0.2 g, 0.636 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) at 0° C. To this reaction mixture was added 1,1-dioxo-thiomorpholine-4-carbonyl chloride slowly and stirred for 2 h at ambient temperature. The solvents were evaporated and the residue purified by preparative HPLC to afford 1,1-dioxo-thiomorpholine-4-carboxylic acid {2-[5-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-benzoimidazol-1-yl]-ethyl}-amide (0.007 g, 2.3%). MS-ESI m/z 476 (M+1); 1H-NMR (300 MHz, CD3OD) δ 1.5 (t, 1H), 1.8 (m, 4H), 2.1 (brs, 3H), 2.8 (s, 4H), 3.6 (t, 2H), 3.8 (s, 4H), 4.2 (m, 2H), 4.5 (t, 2H), 4.7 (s, 1H), 7.5 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.3 (s, 1H). HPLC (VERYPOL.M): tr=6.24 min (97%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 78.9 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 846 mg (4.96 mmol) of 4-anisoyl chloride under ice-cooling with stirring and the mixture was stirred for at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 990 mg of the desired compound (78.9%, colorless powder), mp: 121.0°-122.0° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([F:22])[CH:10]=[CH:11][C:12]=2S(C(F)(F)F)(=O)=O)[O:7][CH2:6]1)[CH2:2][CH3:3].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([F:22])[CH:10]=[CH:11][C:12]=2[C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2c(F)ccc(S(=O)(=O)C(F)(F)F)c2C1
Reactant: OB(O)c1ccco1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCN(CCC)C1COc2c(F)ccc(-c3ccco3)c2C1
Reaction time: 3 h
Yield: 52.9 %

Procedure:
In a three-necked round-bottom flask (25 mL) equipped with a magnetic stirrer and a reflux condensor the following reagents were mixed under nitrogen: 3-dipropylamino-8-fluoro-5-trifluoromethanesulfonylchroman (0.104 g; 0.25 mmol), absolute ethanol (1.7 mL), toluene (3.6 mL), 2-furylboronic acid (0.071 g; 0.64 mmol), lithium chloride (0.022 g; 0.51 mmol), 2M sodium carbonate (0.7 mL) and tetrakis(triphenylphosphine)palladium(0) (0.0073 g). The mixture was heated on an oil-bath to a reflux temperature (75°-80° C.). After 3 hours GC-analysis indicated a partial reaction (20% product and 66% starting material). Therefore more 2-furylboronic acid (0.031 g; 0.28 mmol), absolute ethanol (0.2 mL) and tetrakis(triphenylphosphine)-palladium(0) (0.009 g) were added. The mixture was stirred at 75°-80° C. over night, then poured in 2M ammonia (40 mL) and extracted with ether (2×40 mL). The collected ether phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by flash-chromatography on a silica column with ethyl acetate/n-hexane (2:98). Relevant fractions were pooled and concentrated to give an oil consisting of impure product (72% GC). This material was purified in a second run by flash-chromatography on a silica column eluted with eluted with ethyl acetate/methylene chloride (1:99) to give 0.042 g (51% yield) of 3-dipropylamino-8-fluoro-5-(2-furyl)chroman as an oil.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)C.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[O:6][CH2:5][C:4]([OH:3])=[O:24])=[O:23])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: O=C(O)COc1cccc(NC(=O)c2cc(-c3cccc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (139)(50 mg, 0.13 mmol) was coupled to 3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. During this reaction, hydrolysis occurred and the residue was extracted using Work-up E1. The crude product was then triturated with TBME (2 ml), DCM (2 ml), and recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][NH:38][CH2:39][CH:40]([OH:43])[CH2:41][OH:42].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:43][CH:40]([CH2:41][OH:42])[CH2:39][N:38]([CH3:37])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:34])[F:36])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: CNCC(O)CO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step F (1.2 g, 2.44 mmol) and 3-methylamino-1,2-propanediol (0.32 g, 3.04 mmol) in N,N-dimethyl formamide (10 mL) was added 1-hydroxybenzotriazole (0.36 g, 2.66 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.52 g, 2.71 mmol) followed by N,N-diisopropylethyl amine (0.64 mL, 3.67 mmol). The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown foam. Purification by flash chromatography using a solvent system of 5% methanol in chloroform gave a white foam, which was crystallized from ethyl acetate to provide 1.15 g of title product as a white solid, m.p. 169-172° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]#[C:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[CH3:23][C:24]1[CH:25]=[CH:26][C:27](B2OC(C)(C)C(C)(C)O2)=[C:28]([NH:30]C(=O)OC(C)(C)C)[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:9][C:8]1[C:7]2[N:6]=[CH:5][C:4]([C:10]#[C:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)=[CH:3][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([CH3:23])=[CH:29][C:28]=2[N:30]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: CCOC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)c1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl 4-((5-chloro-6-cyanopyridin-3-yl)ethynyl)benzoate (from the previous step) (1.0 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (2.6 eq.), tetrakis(triphenylphosphine)palladium (10 mol %), and potassium carbonate (5.3 eq.) in toluene/ethanol (2:1, 0.2 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with 2% MeOH in DCM. The two phases were separated. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give ethyl 4-((5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethynyl)benzoate.