Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:22])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:22])[CH3:2]
Reactant: [H][H]
Reactant: CCCC=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1CCC2c3ccc(OCC)c(F)c3OC2C1

Procedure:
5.1 g (about 10.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pent-1-enyl-1,2,3,4,4a,9b-hexahydrodibenzofuran in 50 ml of THF are hydrogenated in a hydrogen atmosphere with addition of 5.0 g of Pd/C (5% Pd). After completion of the uptake of hydrogen (37 h), the reaction solution is filtered and concentrated to dryness. The residue is filtered adsorptively (SiO2, toluene), and the beige solid obtained is re-crystallised repeatedly from isopropanol at room temperature, giving (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-pentyl-1,2,3,4,4a,9b-hexahydro-dibenzofuran as colourless solid (melting point 118° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](Br)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.S1(CCCC1)(=O)=O.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: Brc1ccc2c(c1)Sc1ccccc1CC2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Brc1ccc2c(c1)Sc1ccccc1CC2

Procedure:
10.55 G. 3,11-dibromo-10,11-dihydrodibenzo[b,f]thiepin is suspended in 150 cc. sulfolane and gradually, in portions, 3.5 g. sodium borohydride is added. When the foaming has subsided, water is added and the mixture extracted four times with ether, the combined extracts are washed several times with water, dried and evaporated to dryness, and the residual oil chromatographed on silica gel. On elution with 10% benzene in hexane, 3.31 g. of pure material as a white solid is obtained, m.p. 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[C:59]3=[N:60][CH:61]=[N:62][C:63]([NH2:64])=[C:58]3[CH:57]=[N:56]2)[CH2:51][CH2:50]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[NH2:64][C:63]1[N:62]=[CH:61][N:60]=[C:59]2[N:55]([CH:52]3[CH2:53][CH2:54][N:49]([CH2:16][C:13]4[CH:14]=[CH:15][C:10]([C:8]5[C:7]([C:17]6[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=6)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[N:9]=5)=[CH:11][CH:12]=4)[CH2:50][CH2:51]3)[N:56]=[CH:57][C:58]=12
Reactant: Nc1ncnc2c1cnn2C1CCNCC1
Reactant: Cc1ccc(-c2nc(Cl)c(C#N)cc2-c2ccccc2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4ncc5c(N)ncnc54)CC3)cc2)nc1Cl
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-6-(4-methylphenyl)-5-phenylnicotinonitrile (4-4) (0.204 g, 0.67 mmol), NBS (0.125 g, 0.70 mmol) and benzoylperoxide (0.032 g, 0.13 mmol) in chloroform (5 mL) was heated to reflux for 24 h. Concentrated in vacuo and the residue was dissolved in MeOH (15 mL) and THF (15 mL). To this solution was added 1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.146 g, 0.67 mmol) and diisopropylethylamine (0.433 g, 3.35 mmol). The mixture was stirred overnight and concentrated. The residue was treated with Na2CO3 (20 mL, 2M) and extracted with CH2Cl2. The combined organic layers was dried, filtered and concentrated in vacuo. The solid was purified by silicon gel chromatography (2-4% MeOH in CH2Cl2) to give the title compound. LRMS m/z (M+H) Calcd: 522.03, found: 521.27.
Reaction SMILES: [H-].[Na+].[CH:3](/[C:6]1[C:10]2=[CH:11][CH:12]=[C:13]3[C:22]([NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:23])=[C:9]2[NH:8][C:7]=1[CH:24]=C)=[CH:4]/[CH3:5].Cl[C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]=1>ClCCl>[C:39]1([C:29]2[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:32]=[C:27]([N:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14](=[O:23])[C:13]4[CH:12]=[CH:11][C:10]5[C:6]6[CH:3]=[CH:4][CH:5]=[CH:24][C:7]=6[N:8]([C:27]6[N:32]=[C:31]([C:33]7[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=7)[N:30]=[C:29]([C:39]7[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=7)[N:28]=6)[C:9]=5[C:22]3=4)[N:28]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C=Cc1[nH]c2c(ccc3c(=O)c4ccccc4[nH]c32)c1/C=C\C
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2ccccc2n(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c2c1ccc1c3ccccc3n(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g (75 mmol) of NaH (60% in oil) are initially introduced in 150 ml of dichloromethane. A solution of 8.4 g (28 mmol) of 3-((Z)-propenyl)-2-vinyl-1H,11H-1,11-diazacyclopenta[a]anthracen-6-one in dichloromethane is added dropwise at RT. After 1 h, 17 g (62 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine are added dropwise, and the mixture is stirred at room temperature for 8 h. The solid which has precipitated out is recrystallised from toluene. The crystals which have deposited are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 14.6 g; 70% of theory; purity: 99.9% according to HPLC.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][O:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:13])(=[O:7])=[O:6].[N-:33]=[N+:34]=[N-:35].[Na+]>CS(C)=O>[N:33]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][O:16][C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[O:13])(=[O:7])=[O:6])=[N+:34]=[N-:35]
Reactant: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, (methylethoxycarbonyloxy)methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (27a) (0.14 g, 0.28 mmol) dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 45 mg (0.7 mmol) of sodium azide (NaN3). After work-up, the crude title compound (27) was used in the next step without further purification. MS (ESI) m/z 524.06 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+]>CS(C)=O>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][O:10][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][C:8]=1[CH3:11])[CH:4]=[O:5])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(C=O)c(O)c1O
Reactant: BrCCCOCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C=O)c(O)c1OCCCOCc1ccccc1

Procedure:
Synthesized according to the methods of general procedure 4 in U.S. Pat. Pub. No. 20090227541 (U.S. patent application Ser. No. 12/142,692) using the following reactants and amounts: 2,3-dihydroxy-4-methyl-benzaldehyde (9 g, 59.21 mmol), (3-bromo-propoxymethyl)-benzene (11.5 mL, 65.13 mmol), sodium tert-butoxide (12.52 g, 130.26 mmol) and DMSO (100 mL). Purification: flash column chromatography (5-10% EtOAc/hexane): yield 15.1 g (85%). 1H NMR (400 MHz, CDCl3) δ (ppm): 11.05 (s, 1H), 9.84 (s, 1H), 7.38-7.26 (m, 5H), 7.20 (d, J=7.8 Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.55 (s, 2H), 4.15 (t, J=6.2 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 2.31 (s, 3H), 2.19-2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.C(O)(=O)C.[N:18]([O-])=O.[Na+]>O>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:18][N:4]2[N:3]=1
Reactant: O=N[O-]
Reactant: NNc1nnc(Cl)c2c1CCCC2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Clc1nn2nnnc2c2c1CCCC2

Procedure:
To a suspension of 9.9 g of 1-chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine in 35 ml of aqueous 12% acetic acid was added a solution of 3.5 g of sodium nitrite in 30 ml of water. The mixture was kept at room temperature (about 22°-25° C.) for about 20 minutes. The solid present was then separated by filtration, air dried and recrystallized to give 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:25]([C:27]5[CH:36]=[CH:35][CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=5)=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added methyl 3-formylbenzoate (143 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (220 mg, 62% yield) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH:23]1([C:26]2[N:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[N:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)=[O:21])[O:28][N:27]=2)[CH2:25][CH2:24]1
Reactant: NCc1nc(C2CC2)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: O=C(NCc1nc(C2CC2)no1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-cyclopropyl-1,2,4-oxadiazole-5-methanamine (CAS Registry No. 428507-31-7) as starting materials; LC-MS (UV peak area/ESI) 97.6%, 454.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(F)c2)n1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(F)c2)n1
Yield: 35.4 %

Procedure:
To a solution of 1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (68 mg) in N,N-dimethylformamide (0.7 ml) were sequentially added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (38 mg) prepared in Preparation 1, HOBt.H2O (46 mg) and WSC.HCl (58 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (33 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][N:20]([CH3:60])[C:21]([C:23]3[CH:24]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:59])=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]6)[CH:40]=5)[CH:38]=4)=[O:30])[CH:26]=[CH:27][CH:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:61][CH3:62])=[C:10]([CH2:19][N:20]([CH3:60])[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:38]=[C:37]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:46]6[CH2:47][CH2:48][NH:49][CH2:50][CH2:51]6)[CH:40]=5)[C:36]([F:59])=[CH:35][CH:34]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)C(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(C)C(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-({[(3-{[{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}(methyl)amino]carbonyl}phenyl) carbonyl]amino}methyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.056 g, 0.066 mmol) in DCM (0.25 mL) was added TFA (0.25 mL) which was then stirred at room temperature for 30 min before being diluted with DCM and basified with NaHCO3 (sat. aq.). The organic layer was separated, dried over Na2SO4, filtered, concentrated, purified using a Gilson HPLC (with TFA), and the final product was basified with an amine cartridge to afford 0.047 g (95%) of the title compound. LC-MS m/z 747 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=7.53 Hz, 3 H) 1.50 (t, J=7.28 Hz, 3 H) 1.79-1.92 (m, 2 H) 2.08-2.17 (m, J=12.80, 1.76 Hz, 2 H) 2.93 (s, 3 H) 3.15 (q, J=7.45 Hz, 2 H) 3.56 (s, 8 H) 3.62-3.71 (m, 2 H) 3.98-4.06 (m, J=8.66, 2.89 Hz, 2 H) 4.33-4.42 (m, 1 H) 4.45-4.54 (m, 4 H) 4.61 (s, 2 H) 7.17 (dd, J=10.54, 8.53 Hz, 1 H) 7.38-7.44 (m, J=5.52, 3.01 Hz, 1 H) 7.49-7.63 (m, 4 H) 7.64-7.70 (m, 2 H) 7.74 (s, 1 H) 7.97-8.03 (m, 2 H) 8.32 (s, 1 H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:40]1([C@@H:46]([CH2:48][OH:49])[NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:47][C@@H:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:48][OH:49]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: N[C@H](CO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A solution of N-{5-(bromoacetyl)-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (570 mg) in THF (15 ml) was treated with N,N-diisopropylethylamine (0.41 ml) and (S)-(+)-2-phenylglycinol (191.8 mg). The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting solid was suspended in dry MeOH (15 ml). The resulting suspension was cooled to 0°, treated with calcium carbonate (359 mg) and stirred for 0.5 h. The reaction mixture was treated with NaBH4 (88.8 mg), portionwise at 0° and was then allowed to warm to room temperature and stirred for 64 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE, gradient 0 to 15% [MeOH-ammonia (10:1)] in DCM) to afford the title compound (360 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>ClCCl>[C:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][N:45]([CH3:44])[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3])([CH3:54])([CH3:53])[CH3:52]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNCCC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 125 mg of tert-butyl 3-(methylamino)propanoate, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 209 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow foamed solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][N:28](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[OH-].[K+].CC(O)=O>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:13]4[CH:30]=[CH:29][NH:28][C:14]=4[N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=4)[N:17]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Nc4ccc(C(N)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cn1ncc2cc(Nc3nc(Nc4ccc(C(N)=O)cc4)nc4[nH]ccc34)ccc21
Temperature: 70 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
To a solution of 4-(4-(1-methyl-1H-indazol-5-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (40 mg, 0.072 mmol) in dioxane (2 mL), aq. 1N KOH (1.8 mL, 1.80 mmol) was added. The mixture was stirred at 70° C. for 20 h. HOAc (1.0 mL) was added. The mixture was purified by HPLC to give the titled compound (7 mg). MS 399.2 (M+H) (Compound 25-1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1.[CH2:20]([NH2:22])[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:21]
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCNCCCOc1ccc(C(=O)c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
1.0 g of 4-(3-bromopropyloxy)benzophenone was dissolved in a 70% aqueous ethylamine solution, and then stirred at 90° C. for 5 hours. The mixture was dissolved in 50 ml of chloroform, washed with water three times, dried over anhydrous sodium sulfate and then concentrated to obtain 0.9 g of N-ethyl-3-(4-benzoylphenyloxy)propylamine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([C:14]4[CH:19]=[C:18]([CH:20]=O)[CH:17]=[C:16]([O:22][CH3:23])[C:15]=4[O:24][CH3:25])[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[NH:31]([CH2:38][CH2:39][C:40]#[N:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC([O-])(C)C.[K+].Cl>CS(C)=O.O>[C:40]([C:39](=[CH:38][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[C:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH:19]=1)#[N:41]
Reactant: COc1cc(C=O)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Reactant: N#CCCNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 310 mg of 1-cyclopropyl-6-fluoro-7-(5-formyl-2,3-dimethoxy-phenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (Example 8a)) in 3 ml of dimethyl sulphoxide is treated with 110 mg of 3-anilinopropionitrile and 185 mg of potassium tert-butylate. The resulting solution is stirred at room temperature for one hr. The reaction mixture is poured into 30 ml of water, adjusted to pH 5 with 2N aqueous HCl and extracted twice with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water and with 50 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. 400 mg (98%) of 7-[5-(2-cyano-3-phenylamino-allyl)-2,3-dimethoxy-phenyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained as a yellow foam.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH:15]([C:20]1[CH:21]=[C:22]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:23]=[C:24]([O:26]CC2C=CC=CC=2)[CH:25]=1)[CH2:16][C:17]([CH3:19])=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([CH:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH:15]([C:20]1[CH:21]=[C:22]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:38][CH:39]=2)[CH:23]=[C:24]([OH:26])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 94.3 %

Procedure:
To a solution of 4-benzyl-3-[2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.7 g, 11.2 mmol) in MeOH (150 mL) was added 10% Pd/C (670 mg, 10 w %). The black suspension was hydrogenated at 45-45 psi overnight. The mixture was filtered through celite and the solvent was remixed in vacuo to obtain relatively pure 4-benzyl-3-[2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazolidin-2-one (5.4 g, 93%).