Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]([CH3:48])([CH3:47])[CH2:8][C:9]([O:11][C@H:12]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@:17]3([CH3:44])[C@@H:26]2[CH2:25][CH2:24][C@H:23]2[C@@:18]3([CH3:43])[CH2:19][CH2:20][C@@:21]3(/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41])[CH2:33][C:32](=[O:34])[C:31]([CH:35]([CH3:37])[CH3:36])=[C:22]32)[C:13]1([CH3:46])[CH3:45])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:40](/[CH:39]=[CH:38]/[C@:21]12[CH2:33][C:32](=[O:34])[C:31]([CH:35]([CH3:37])[CH3:36])=[C:22]1[C@@H:23]1[C@@:18]([CH3:43])([CH2:19][CH2:20]2)[C@@:17]2([CH3:44])[C@@H:26]([C@:27]3([CH3:30])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:46])([CH3:45])[C@@H:12]([O:11][C:9](=[O:10])[CH2:8][C:7]([CH3:47])([CH3:48])[C:6]([OH:49])=[O:5])[CH2:29][CH2:28]3)[CH2:25][CH2:24]1)([OH:42])=[O:41]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a solution of (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-((4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoyl)oxy)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylic acid (200 mg, 0.294 mmol) in dichloromethane (6 mL) stirred at room temp was added trifluoroacetic acid (TFA) (3 mL). The reaction mixture was stirred at 20° C. for 1 h. The product was extracted with DCM (15 mL*3) and the residue was purified by preparative-HPLC to give the title compound (85 mg, 39%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.05 (d, J=16.1 Hz, 1H), 5.75 (d, J=16.3 Hz, 1H), 4.52 (dd, J=4.8, 11.3 Hz, 1H), 3.32-3.11 (m, 1H), 2.78-2.61 (m, 3H), 2.34-2.12 (m, 3H), 2.06-0.61 (m, 44H); LC/MS: m/z calculated 624.4. Found 625.3 (M+1)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2N)cc1
Temperature: -7.5 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a stirred solution of (R,R)-1,2-diaminocyclohexane (300 g, 2.63 mole) in CH2Cl2 (5.00 l) at −10° C. was added a solution of p-toluenesulfonylchloride (209 g, 1.10 mole) in CH2Cl2 (5.00 l) dropwise over a 7 h period, maintaining the temp at −5 to −10° C. The mixture was allowed to warm to room temp while stirring overnight. The mixture was concentrated in vacuo to a volume of 3 l and the white solid was removed by filtration. The solution was then washed with H2O (10×1 l) and was dried over MgSO4. Removal of the solvent in vacuo gave 286 g (97.5% yield) of the product as a yellow crystalline solid: 1H NMR (CDCl3) δ 0.98-1.27 (m, 4H), 1.54-1.66 (m, 2H), 1.81-1.93 (m, 2H), 2.34 (dt, J=4.0, 10.7 Hz, 1H), 2.42 (s, 3H), 2.62 (dt, J=4.2, 9.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H); MS (LRFAB-DTT-DTE) m/z 269 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([CH2:16]O)[CH:10]=[CH:9]2.CO>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:3][CH2:16][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([Cl:5])[CH:7]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2cc(Cl)ccc2c1
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2cc(Cl)ccc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Thionyl chloride (99.4 g.) is added dropwise at 0° C. during 1 hour to a stirred suspension of the 6-chloro-2-hydroxymethylnaphthalene (96.3 g.) in a mixture of pyridine (50.0 g.) and chloroform (2 l.). The mixture is stirred for 1 hour at 20° C., then treated dropwise with methanol (60 ml.) and stored for 18 hours. The solution is washed with water, 3N-hydrochloric acid, and water again, dried with magnesium sulphate and evaporated. The residue is crystallised from light petroleum (b.p. 80°-100° C.) to give 2-chloromethyl-6-chloronaphthalene (101 g.) m.p. 107°-110° C. raised to 110°-111° C. by further crystallisation.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:17]=[C:16]([C:18]([N:20]2[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21]2)=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+].C1COCC1.Cl>O>[F:26][C:22]1([F:25])[CH2:23][CH2:24][N:20]([C:18]([C:16]2[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=2)[C:4]([OH:27])=[O:3])=[O:19])[CH2:21]1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCC(F)(F)C2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)N2CCC(F)(F)C2)c1
Yield: 104.1 %

Procedure:
Stir a solution of 5-(3,3-difluoropyrrolidine-1-carbonyl)-N-methyl-N-propyl-isophthalamic acid ethyl ester (270 mg, 0.71 mmol), 1 N lithium hydroxide (1.1 mL, 1.1 mmol) and THF (2.0 mL) at room temperature for 4 h. Add 10 mL water, acidify with 1 N HCl (2 mL), extract with dichloromethane (3×10 mL), dry (sodium sulfate) and concentrate to give the title compound (262 mg, 100%).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Br:13]Br.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:13][C:9]1[CH:10]=[C:5]([NH:1][C:2]([CH3:4])=[O:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(NC(C)=O)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 10.0 g (60.5 mmol) of 4-acetaminoanisole (5) in 80 mL of acetic acid, was added dropwise 11.6 g (72.7 mmol) of bromine and maintaining internal temperature of the reaction below 50° C. After stirring for 1 h, the reaction mixture was poured into 400 mL of ice-water containing 1.2 g of NaHSO3. The mixture was stirred until yellow-red color disappeared and left at room temperature for overnight. The solid (product) was filtered, dried under vacuum at 70° C., and crystallized from ethanol to give 10.19 g (69% yield). 1H NMR (CDCl3) δ 7.67 (d, J=2.5 Hz, 1 H), 7.44 (dd, J=9, 2.5 Hz, 1 H), 7.1 (bs, 1 H, NH), 6.85 (d, J=9 Hz, 1 H), 3.87 (s, 3 H, OMe), 2.16 (s, 3 H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][C:15]([C:17]2([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:9][S:10](=[O:13])(=[O:12])[NH2:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:32][C:17]1([C:15]([NH:14][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][S:10](=[O:12])(=[O:13])[NH2:11])=[O:16])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(CS(N)(=O)=O)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
Tert-butyl 4-(1-(4-chlorophenyl)-2-sulfamoylethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 81) (153 mg, 0.26 mmol) was treated with trifluoroacetic acid (4 mL). The solution was stirred for 30 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using ammonia in methanol (2M) and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-sulfamoylethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (125 mg, 99%) as a colourless solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH3:26][N:24]1[CH:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][C:8]4[CH:9]=[CH:10][C:5]5[N:6]([C:2]([C:31]6[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=6)=[CH:3][N:4]=5)[CH:7]=4)=[CH:13][N:14]=3)[N:17]=2)[CH:22]=[N:23]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(Br)n5c4)n3n2)cn1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncc(-c6cnn(C)c6)n5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
3-(3-Bromo-imidazo[1,2-a]pyridin-6-ylmethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 296, 77 mg, 0.189 mmol) was dissolved in DME (0.629 mL) with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39.2 mg, 0.189 mmol), 2 M Na2CO3 solution (0.339 mL, 0.679 mmol) and tetrakis(triphenylphosphine)palladium (10.9 mg, 0.009 mmol). The RM was heated at 150° C. 5 min under microwave irradiations. It was taken up with EtOAc and washed with 10% Na2CO3 solution and brine. Then it was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and passed through an SPE cartridge of PL-Thiol MP to remove the palladium. Then the filtrate was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and acetonitrile was removed. The aqueous solution was basified with 5% NaHCO3 solution and was extracted with EtOAc twice. Combined organic layers was washed with brine and dried over Na2SO4. It was filtered to afford after evaporation of the solvent the title compound as a white solid (tR 0.7 min (conditions 2), MH+=410).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:13]=[C:12]3[NH:29][N:30]=[C:31]([C:32]#[N:33])[C:11]=23)=[CH:6][CH:5]=1.O.CC[O:37]C(C)=O>CC(O)(C)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:13]=[C:12]3[NH:29][N:30]=[C:31]([C:32]([NH2:33])=[O:37])[C:11]=23)=[CH:6][CH:5]=1
Reactant: N#Cc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: NC(=O)c1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)c12
Yield: 28 %

Procedure:
A solution of KOH (0.07 g, 1.3 mmol) in tBuOH (2.5 mL) was added under argon atmosphere to 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (0.05 g, 0.1 mmol, obtained in example 65) and heated to reflux overnight. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 15 mg of the title compound in solid form (yield: 28%)
Reaction SMILES: C(OC([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([NH2:12])=O)=O)(C)(C)C.C(OC(C)C)(=O)C.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>O>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[F:16][C@@H:14]1[CH2:15][NH:8][C@H:9]([C:10]#[N:12])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)C
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#C[C@@H]1C[C@H](F)CN1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:5]([NH:7][OH:8])=[NH:6].[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[CH3:21])[O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15]
Reactant: CCC(CC)Oc1ccc(C(=N)NO)cc1Cl
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCC(CC)Oc1ccc(-c2noc(-c3ccccc3C)n2)cc1Cl
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a solution of 3-chloro-4-(1-ethyl-propoxy)-N-hydroxy-benzamidine (64 mg, 0.25 mmol) (prepared by General procedure B) in pyridine (1 mL) was added a solution of 2-methylbenzoyl chloride (77 mg, 0.5 mmol) in pyridine (1 mL). The mixture was heated at about 100° C. overnight. The solvent was removed under reduced pressure and the crude product was purified via SFC(CO2/pure MeOH; gradient: 5% hold for 0.5 min, ramp at 7.3% to 50% over 6.5 min, hold at 50% for 1 min) to give 3-[3-chloro-4-(1-ethyl-propoxy)-phenyl]-5-o-tolyl-[1,2,4]oxadiazole (16.5 mg, 18.5%).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+:20].[Cl-].[Na+]>O>[OH2:8].[NH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[CH2:11][C:12]([O-:18])=[O:19].[Na+:20]
Reactant: [OH-]
Reactant: O=C1Cc2c(cccc2C(=O)c2ccccc2)N1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1cccc(C(=O)c2ccccc2)c1CC(=O)[O-]
Reaction time: 12 h

Procedure:
A suspension of 4.5 g. (0.0190 mole) of 4-benzoylindolin-2-one in 200 ml. of 3 N sodium hydroxide was refluxed under a nitrogen atmosphere for 4 hr. The volume of water was reduced by approximately half, and the solution saturated with sodium chloride. The solution was chromatographed on a 230 ml. (wet volume) column of Amberlite XAD-2 ion exchange resin packed in distilled water. The product precipitated on the top of the column packing, but dissolved as the column was eluted with distilled water. The fractions containing the product were collected, combined, and the solvent removed under reduced pressure to give 4.6 g. of solid. Recrystallization from methanol-ether gave 0.91 g. of a yellow solid, m.p. 256.5°-258.5° C. (dec.). The filtrate was evaporated under reduced pressure and the residue was dissolved in hot isopropanol by adding a small amount of water. The hot solution was filtered to remove a suspended solid. The filtrate seeded and placed in the freezer for 12 hr. The pale yellow solid which separated was collected by filtration and yielded 2.84 g. (50.3%) of product, m.p. 254.5°-256° C. (dec.). A portion of the bulk product was dried under high vacuum at room temperature.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].C(=O)(O)[O-].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:23](=[O:24])[O:25][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccc(Cl)cc1Cl
Yield: 35.5 %

Procedure:
To a stirred slurry of 1-amino-2-(2,4-dichlorobenzoyl)pyrrole (377.6 g) and sodium bicarbonate (286.0 g) in 2.0 L of dichloromethane was added ethyl chloroformate (176.90 g) over 10 min. The reaction mixture was heated at reflux for 4 hrs and then quenched with H2O. The organic layer was washed with brine, dried (MgSO4), charcoaled, filtered and concentrated to a maroon oil. This oil was purified by flash chromatography (silica, dichloromethane) and concentrated to a green powder which was recrystallized from ether to give 171.8 g of white crystals, mp 114°-116°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C@@H:8]1[CH2:20][CH3:21].C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][C@@H:8]1[CH2:20][CH3:21])=[O:45]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CC[C@H]1CNCCN1c1c(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cnn1C
Yield: 19 %

Procedure:
Following the procedure for Example 112, reacting (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 gave 113 as a white solid (27 mg, 19% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.91 (s, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.03 (t, J=9.2 Hz, 2H), 6.20 (s, 2H), 3.77 (s, 3H), 3.24-3.14 (m, 2H), 3.12-2.93 (m, 4H), 2.60 (t, J=10.8 Hz, 1H), 1.48-1.28 (m, 1H), 1.28-1.16 (m, 1H), 0.79 (t, J=7.6 Hz, 3H). Alkyl NH not observed. LCMS (ES+) m/z 448 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].C(OC(=O)C)(=O)C.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c2c1CCC2=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1CCC2=O

Procedure:
Into a solution of 25.6 g of 4-methyl-7-hydroxy-1-indanone in 250 ml of acetic acid was added 19.4 ml of acetic anhydride and a solution of 15.4 ml of concentrated nitric acid in 50 ml of acetic acid gradually. The reaction mixture was concentrated to drynsss, and the residue was washed with ether to obtain 25.7 g of 4-methyl-6-nitro-7-hydroxy-1-indanone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:36]([O:37][CH3:38])=[CH:35][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:36]([O:37][CH3:38])=[CH:35][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CCO)CC2
Yield: 61 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. Product was isolated as a white foam (58 mg, 61%). MS (ESI+): 546.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.23 (s, 1H), 8.58 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8 Hz, 1H), 7.62 (t, J=7 Hz, 1H), 7.52 (s, 1H), 6.68 (s, 1H), 3.90 (s, 3H), 3.65 (t, J=5 Hz, 2H), 3.28 (m, 1H), 2.89 (m, 2H), 2.73-2.67 (m, 8H), 1.34 (d, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][C:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)=[CH:15][CH2:14]2)[C:3]1=[O:29].C(O)(=O)C.[H][H].[ClH:37]>C(O)C.[Pt]=O.C>[ClH:37].[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([F:28])[CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:17][CH2:18]2)[C:3]1=[O:29]
Reactant: CC1(C)C(=O)N(CCN2CC=C(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)C(=O)N(CCN2CCC(c3c[nH]c4c(F)cccc34)CC2)c2ccccc21

Procedure:
3,3-Dimethyl-1-{2-[4-(7-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-1,3-dihydro-2H-indol-2-one (0.6 g, 1.36 mmol) dissolved in ethanol (40 mls) and acetic acid (4 mls) was added to 10% platinum oxide/charcoal. Hydrogen was admitted for 12 h at 60 psi the catalyst was then removed by filtration, the catalyst washed with ethanol (3×75 mls), concentrated in vacuo and the resulting oil purified by column chromatography on silica with ethyl acetate/Hexane. The fractions containing product were collected and the solvent evaporated in vacuo to give a solid which was converted to the hydrochloride, which was subsequently dried in vacuo to give a solid, mp 172-174° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([CH3:29])[CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(C)C)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(propan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f54) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.