Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[OH:33]OS([O-])=O.[K+].Cl>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([OH:33])=[O:31])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=S([O-])OO
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a suspension of aldehyde 47 (200 mg, 0.446 mmol) in DMF (10 mL) was added Oxone® (330 mg, 0.535 mmol) at RT and the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was cooled to 0° C., treated with 1N aqueous HCl (20 mL) and stirred at RT for an additional hour. The resultant precipitate was collected by filtration, washed with water (30 mL) and dried. The crude product was triturated with MeOH to afford title compound 225 (165 mg, 80% yield) as a beige solid. NMR (400 MHz, CD3OD) δ (ppm): 9.66 (bs, 1H), 8.98 (dd, J=1.9, 0.9 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.22 (dd, J=8.1, 1.9 Hz, 1H), 8.17 (dd, J=8.1, 0.9 Hz, 1H), 7.77 (dd, J=13.7, 2.5 Hz, 1H), 7.45 (bs, 1H), 7.37 (t, J=9.1 Hz, 1H), 7.26 (dd, J=8.9, 1.5 Hz, 1H), 6.62 (d, J=5.3, 0.8 Hz, 1H), 2.60-2.52 (m, 1H), 0.69-0.56 (m, 2H), 0.50-0.37 (m, 2H). [Carboxylic OH is not seen]. MS: 465.3 (MH)+
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[C:6]([CH:10]1[CH:15]([OH:16])[CH2:14][CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11]1)([O:8][CH3:9])=[O:7]>CCOCC>[C:6]([CH:10]1[CH2:11][C:12]([CH3:18])([CH3:17])[CH2:13][CH2:14][CH:15]1[O:16][CH:1]([CH3:2])[O:3][CH2:4][CH3:5])([O:8][CH3:9])=[O:7]
Reactant: C=COCC
Reactant: COC(=O)C1CC(C)(C)CCC1O
Solvent: CCOCC
Product: CCOC(C)OC1CCC(C)(C)CC1C(=O)OC
Yield: 98 %

Procedure:
Ethyl vinyl ether (10.5 g) were added slowly and dropwise to 50 ml of Et2O containing 6-carbomethoxy-4,4-dimethylcyclohexan-1-ol (25 g) at 0° C. under nitrogen. After 30 minutes the mixture was washed with saturated aqueous NaHCO3. After distillation (Bp 110-120° C./10 torr) were obtained 34 g of 2-carbomethoxy-4,4-dimethyl-1-(2-methyl-1,3-dioxapent-1-yl)cyclohexane (yield 98%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]2[C:10]=1[C:9](=O)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:6]2.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:9]1[C:10]2=[C:2]([CH3:1])[N:3]=[C:4]([CH3:18])[N:5]2[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=1
Reactant: Cc1nc(C)n2nc(-c3ccccc3)[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(C)n2nc(-c3ccccc3)nc(Cl)c12

Procedure:
700 mg (2.9 mmol) of 5,7-dimethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 15A) were dissolved in 8 ml of phosphoryl chloride and stirred at reflux for 12 h. The reaction mixture was poured into 170 ml of saturated sodium bicarbonate solution, and solid sodium bicarbonate was added until a pH of 7 had been reached. Ethyl acetate was added, and the mixture was extracted. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated on a rotary evaporator. This gave 657 mg (80% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[CH:5][C:6]=1[CH2:7]O.P(Br)(Br)[Br:49].N1C=CC=CC=1>CCOCC>[CH2:32]([O:31][C@H:12]1[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([C:4]2[S:3][C:2]([Cl:1])=[C:6]([CH2:7][Br:49])[CH:5]=2)[O:10][C@@H:11]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Clc1sc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
To a solution of alcohol 37 (3.86 g, 5.75 mmol) in ether (50 mL) were added phosphorus tribromide (0.3 mL, 2.88 mmol) and catalytic amount of pyridine at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc/H2O (100 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 38 (4.1 g, 97%), which was carried on to the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2([C:21]([OH:23])=O)[C:15]3[C:20]([CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=42)[CH2:6]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2].S(Cl)([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][CH:5]1[C:14]2([C:21]([Cl:26])=[O:23])[C:15]3[C:20]([CH:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=42)[CH2:6]1)=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC2c3ccccc3C1(C(=O)O)c1ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)OC1CC2c3ccccc3C1(C(=O)Cl)c1ccccc12

Procedure:
A solution of 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid (1.0 g) in benzene (10.0 ml) and thionyl chloride (4.0 ml) was refluxed for 4 hours. Evaporation of excess thionyl chloride and benzene gave 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid chloride. The acid chloride was dissolved in dry acetone (25.0 ml), and a solution of sodium azide (0.63 g) in water (1.3 ml) was added thereto while ice cooling. The resulting mixture was stirred while ice cooling for 2 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate, refluxed for 2 hours and evaporated to dryness to give 9-isocyanato-12-acetoxy-9,10-dihydro-9,10-ethanoanthracene.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (6.34 g, 40 mmol), 3-amino-4-fluorophenol (5.08 g, 40 mmol), potassium carbonate (5.52 g, 40 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the Mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was to concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (7.90 g, 79%) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]2[N:40]([CH3:41])[N:39]=[CH:38][CH:37]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 50.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (79.1 mg, 0.131 mmol) prepared in Example 20b, triethylsilane (0.05 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (30.0 mg, 51%) as a colorless solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=2)[C:3]1=[O:21].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](Cl)=[O:32])[CH:26]=[C:27]([F:29])[CH:28]=1>>[Br:20][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:11][N:2]([NH:1][C:31](=[O:32])[CH2:30][C:25]3[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=3)[C:3]2=[O:21])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1cc(F)cc(F)c1
Reactant: COc1ccc(-c2nn(N)c(=O)c3cc(Br)ccc23)cc1
Product: COc1ccc(-c2nn(NC(=O)Cc3cc(F)cc(F)c3)c(=O)c3cc(Br)ccc23)cc1

Procedure:
The product from Example 174A and 2-(3,5-difluorophenyl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.77-11.80 (bs, 1H), 8.49 (d, J=2.1 Hz, 1H), 8.15 (dd, J=8.6, 2.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.51-7.55 (m, 2H), 7.06-7.22 (m, 5H), 3.85 (s, 3H), 3.76-3.77 (bs, 2H); MS (ESI+) M/Z 503 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C>CC(C)=O>[C:28]([CH2:27][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1)#[N:29]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: N#CCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCNc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulphamyl-benzoic acid (1 g), chloroacetonitrile (0.625 g), triethylamine (0.28 g), and dry acetone (10 ml) was refluxed for 19 hours. After cooling, the precipitated triethylamine hydrochloride was removed by filtration, and the filtrate was evaporated in vacuo. To the residue, water (20 ml) and ethylacetate (50 ml) were added, and the pH of the aqueous layer was adjusted to pH 7.5. The organic layer was then separated, washed with dilute sosium hydrogen carbonate, dried, and evaporated in vacuo. The residue was recrystallized several times from chloroform/petroleum ether. Thereby the cyanomethyl-3-n-butylamino-4-phenoxy-5-sulphamyl-benzoate was obtained with a melting point of 159°-161° C.
Reaction SMILES: C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14](Br)=[CH:13][N:12]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>CO.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>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[C:14]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[CH:13][N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N)ncc2Br)CC1
Reactant: COc1ccc(B(O)O)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: [Na+]
Solvent: CO
Solvent: CC#N
Product: COc1ccc(-c2cnc(N)cc2NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
Acetonitrile (1212 μL) and 0.5M sodium carbonate solution (0.36 mL, 1.5 eq) were added to tert-butyl 4-(2-amino-5-bromopyridin-4-ylamino)piperidine-1-carboxylate (45 mg, 0.121 mmol), 4-methoxyphenylboronic acid (27.6 mg, 0.182 mmol), and tetrakis(triphenylphosphine)palladium(0) (7.00 mg, 6.06 μmol) in a microwave vial (0.5 mL). The capped vial was heated to 150° C. by microwave irradiation for 20 min. After cooling the solution was diluted with MeOH and purified by ion exchange on SCX-II acidic resin (2 g) column, eluting with MeOH then 2M ammonia in MeOH. The basic fractions were combined and concentrated. The crude product was dissolved in dichloromethane and loaded onto a Biotage SNAP silica column (10 g) which was eluted with a gradient of MeOH/NH3 (99/1) in dichloromethane to give tert-butyl 4-(2-amino-5-(4-methoxyphenyl)pyridin-4-ylamino)piperidine-1-carboxylate (19 mg, 0.048 mmol, 39%) as a colourless foam.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([F:23])[CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:19])=[C:16]([F:23])[CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mmol) in toluene (10 mL) and reflux for 2 h. Evaporate the reaction mixture to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and use for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0° C. and add a solution of 4-bromo-2-fluoro-benzoyl chloride (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). Stir the reaction mixture at 0° C. for 10 min, warm to ambient temperature and continue to stir for 30 min. Wash the reaction mixture with brine (2×10 mL), dry the organic extracts over anhydrous Na2SO4, evaporate the solvent and purify by chromatography on silica gel eluting with DCM to obtain the desired intermediate as a white solid (1.0 g, 87%). MS (ES+) m/z: 275 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)=[O:35])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 33.9 %

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-fluorophenyl isocyanate (83 mg, 0.61 mmole), 65 mg (33% yield) of the title product was isolated as white solid. (M+H)=480.3
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([CH2:22][C:23](OCC)=[O:24])[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]2=[O:32]>>[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[N:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:18]2=[O:32]
Reactant: CCOC(=O)CC1c2c(F)cccc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2cccc(F)c2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 21.4 %

Procedure:
N-[(7-Fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.29 g of potassium tert-butoxide, 1.32 g of guanidinium chloride and 0.67 g of ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, and is then filtered. The filtrate is taken up in 40 cm3 of water and 60 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted with twice 60 cm3 of ethyl acetate. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 55° C. The evaporation residue is taken up in diethyl ether and concentrated to dryness again under the same conditions, and then taken up in water and concentrated to dryness again under the same conditions. The residue is purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 15-40 μm), eluting with a mixture of dichloromethane/methanol (90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is taken up in diisopropyl ether, triturated, filtered and then dried. 0.15 g of N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a pale yellow solid melting at 205° C. 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.74 (d, J=6.5 Hz: 3H); 0.89 (d, J=6.5 Hz: 3H); 2.06 (mt: 1H); 2.38 (dd, J=15 and 7.5 Hz: 1H); 2.90 (dd, J=15 and 4.5 Hz: 1H); 3.04 (dd, J=13.5 and 4.5 Hz: 1H); 3.56 (dd, J=13.5 and 10 Hz: 1H); 5.23 (dd, J=7.5 and 4.5 Hz: 1H); from 6.20 to 7.00 (broad multiplet: 2H); from 7.35 to 7.60 (mt: 3H); from 7.50 to 8.20 (broad multiplet: 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=O)(=[O:30])=[O:29])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:68]1[CH2:73][CH2:72][O:71][CH2:70][CH2:69]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[O:34])(=[O:29])=[O:30])=[CH:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)N3CCOCC3)s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Prepared using General Procedure 16: To (R)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 158 (15 mg, 0.03 mmol) in DCM (0.4 mL) was added HATU (26 mg, 0.07 mmol) and DIEA (7.8 mg, 0.06 mmol). After 30 min, morpholine (52 mg, 0.6 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was quenched with water (100 μL) and the solvent evaporated. The crude material was purified by preparative HPLC to afford 8 mg (47%) of (R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-morpholino-2-oxoethanesulfonamide 162. LCMS-ESI (m/z) calculated for C28H30N4O5S2: 566.1; found 567.2 [M+H]+, tR=3.77 min.
Reaction SMILES: [BH4-].[Na+].[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][C:29](OC)=[O:30])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO>O1CCCC1>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30])[CH:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)CSCCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
0.21 g of sodium borohydride was added to a solution of 1.98 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-5-(methoxycarbonylmethylthio)pentanamide [prepared as described in step (b) above] in 40 ml of tetrahydrofuran, and 8 ml of methanol were added dropwise to the mixture, whilst ice-cooling; it was then stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was mixed with water. The resulting aqueous mixture was extracted with ethyl acetate, and the extract was freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 1.51 g (yield 63%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[N+:16]([O-])=O)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[NH2:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(CC(N)C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1ccc(CC(N)C(=O)O)cc1N

Procedure:
3-(4-acetyl-3-nitrophenyl)-2-aminopropanoic acid was reduced by 5% Pd on carbon in MeOH under 1 atm H2. Filtration followed by concentration under reduced pressure afforded 3-(4-Acetyl-3-aminophenyl)-2-aminopropanoic acid (X3179-96). MS (ESI+): m/z 223.22 (MH+). 1H NMR (400 MHz, MeOD): δ 7.78 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.25 (dd, J′=8.4 Hz, J″=5.2 Hz, 1H), 3.23 (dd, J′=14.4 Hz, J″=5.2 Hz, 1H), 3.02 (dd, J′=14.4 Hz, J″=8.4 Hz, 1H), 2.54 (s, 3H); 13C NMR: δ 202.14, 171.20, 152.93, 142.51, 134.40, 118.78, 118.23, 116.91, 54.63, 37.42, 27.90.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.[BH4-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]([OH:12])[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: O=C1Cc2ccccc2Sc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1Cc2ccccc2Sc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17 G. of 3-bromo-10,11-dihydro-11-oxodibenzo[b,f]thiepin (0.056 mole) are dissolved in a mixture of 150 cc. DMF and 150 cc absolute alcohol. 1.7 G. sodium borohydride (0.045 mole) are added and the mixture is left stirring overnight at room temperature. The ethanol is evaporated and the residual DMF solution is diluted with water and extracted with ether three times. The ether extracts are washed several times with water, dried and evaporated to a thick oil. A quantitative yield of the alcohol is obtained.